Anna Passarelli1*
Sabrina Chiara Cecere1
Jole Ventriglia1Carmela Pisano1Rosella De Cecio2Sabrina Rossetti1Rosa Tambaro1Marilena Di Napoli1Lorenzo Lobianco1,3
Gabriele Calvanese1,4Maria Rosaria Lamia1,5Erica Perri1,3Maria Sara Peluso1Emilia Scarpa1Salvatore Stilo6
Francesco Fiore6Sergio Venanzio Setola7Daniela Califano8
Sandro Pignata1- 1Department of Urology and Gynecology, Istituto Nazionale Tumori Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Fondazione G. Pascale, Naples, Italy
- 2Division of Anatomic Pathology and Cytopathology, Istituto Nazionale Tumori Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Fondazione G. Pascale, Naples, Italy
- 3Medical Oncology, Department of Precision Medicine, University of Campania Luigi Vanvitelli, Naples, Italy
- 4Department of Oncology and Hemato-Oncology, Università degli Studi di Milano, Milan, Italy
- 5Department of Clinical Medicine and Surgery, University Federico II, Naples, Italy
- 6Interventional Radiology Unit, Istituto Nazionale Tumori Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Fondazione G. Pascale, Naples, Italy
- 7Radiology Unit, Istituto Nazionale Tumori Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Fondazione G. Pascale, Naples, Italy
- 8Microenvironment Molecular Targets Unit, Istituto Nazionale Tumori Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Fondazione G. Pascale, Naples, Italy
Ovarian clear cell carcinoma (OCCC) is a rare, aggressive epithelial ovarian cancer subtype, accounting for approximately 10% of cases and associated with a poor prognosis due to chemoresistance and unique tumor biology. OCCC is frequently linked to endometriosis and characterized by mutations in ARID1A and PIK3CA, hyperactivation of the PI3K/Akt/mTOR pathway, and overexpression of VEGF, HIF-1α, and IL-6. These features drive tumor proliferation, angiogenesis, immune evasion, and resistance to platinum-based chemotherapy. The tumor microenvironment of OCCC is highly immunosuppressive, with infiltration of regulatory T cells, tumor-associated macrophages, and upregulation of immune checkpoint molecules, such as PD-1, PD-L1, and LAG-3. These characteristics suggest that the PD-1/PD-L1 pathway plays a critical role in tumor immune evasion and could be an attractive target for therapeutic intervention. Despite the typical composition of the immunosuppressive tumor microenvironment in ovarian cancer, until now overall the results of trials testing immune checkpoint inhibitors so far have been disappointing. It is interesting to note instead that several subgroup analyses reported exceptional OCCC sensitivity to ICIs. Indeed, current and preliminary trials exploring ICIs, anti-angiogenic agents, and combinatorial therapies in OCCC show promising outcomes. Strategies targeting multiple pathways, including VEGF, IL-6, HIF-1α, and HDAC6, alongside ICIs, are under investigation to overcome resistance mechanisms. Additionally, IL-10 inhibition or ferroptosis pathway activation offers novel therapeutic potential. Personalized, biomarker-driven approaches, targeting ARID1A and PIK3CA mutations or combining immune and anti-angiogenic agents, are gaining traction in OCCC management. This review highlights OCCC molecular underpinnings and therapeutic challenges, emphasizing the need for innovative, multi-targeted strategies. Advances in understanding genetic-immunological interplay in OCCC may enable more effective and durable treatments and improved patient outcomes.
1 Introduction
Epithelial ovarian carcinoma (EOC) is the deadliest gynecological malignancy and among the leading contributors to cancer-related mortality in women worldwide (1). Up to 90% of ovarian neoplasms are classified as EOC, further divided into the following subtypes based on histopathology: high-grade serous carcinomas, the most prevalent, comprising about 70% of cases; low-grade serous carcinomas, accounting for less than 5%; endometrioid carcinomas (EC), representing 10%; clear cell carcinomas (CCC), also accounting for 10%; and mucinous carcinomas, comprising 3% (2). Ovarian clear cell carcinoma (OCCC) is thought to arise from the malignant transformation of ectopic endometrial tissue located on the ovary. This is supported by the presence of endometriosis in 50–70% of OCCC cases (3), linked to a 2.3-fold increased risk of OCCC development (4–6). As a result, OCCC, along with EC, is classified as an endometriosis-associated ovarian cancer (7–10). OCCC represents a distinct pathological subtype, typically presenting as a large, unilateral pelvic mass that, on histopathological examination, displays a combination of papillary, tubulocystic, and solid growth patterns, along with clear and eosinophilic cells and stromal hyalinization (11). Notably, the presence of intracellular glycogen deposits is a highly distinctive diagnostic feature (12). This subtype exhibits poor responsiveness to platinum-based chemotherapy and is associated with worse outcomes than other EOC subtypes (10, 13). Furthermore, cancer-associated thromboembolism, a vascular thromboembolic complication, occurs more frequently in OCCC than in other histologic EOC subtypes, contributing to an unfavorable prognosis (14–17). When diagnosed at an advanced stage, OCCC is associated with shorter progression-free survival (PFS) and overall survival (OS) and poor chemotherapy response (18). Among patients diagnosed at FIGO stages I–II, OS rates are 80–89%, and PFS ranges from 56% to 88%. In contrast, for FIGO stages III–IV, OS drops to 52%, and PFS declines to 25% (19–22). Interestingly, OCCC is characterized by a typical tumor microenvironment (TME) with a strong immunosuppressive milieu. These characteristics suggest that the PD-1/PD-L1 axis is a key mechanism in tumor immune evasion and represents a potentially valuable target for therapeutic intervention. Although clinical trials evaluating immune checkpoint inhibitors (ICIs) in advanced ovarian cancer have so far produced mostly disappointing results, several subgroup analyses have identified a marked sensitivity of the clear cell ovarian carcinoma (OCCC) histotype to ICIs.
This review further clarifies the unique molecular signature and TME features of OCCC, focusing primarily on the promising role played by the use of immunotherapy.
2 Methods
Papers to be considered were identified by conducting PubMed searches, using different combinations of pertinent keywords “ovarian clear cell carcinoma,” “OCCC,” “immune checkpoint inhibitors,” “PD-1,” “PD-L1,” “LAG-3,” “ARID1A,” “PIK3CA”, “VEGF,” “tumor microenvironment,” “immune evasion,” “immunosuppression,” “HIF-1α,” “IL-6,” “angiogenesis,” “ferroptosis,” “HDAC6,” “clinical trials,” and “immunotherapy”. Boolean operators (AND, OR) were used to refine the search. Clinical trial data were retrieved from ClinicalTrials.gov using the keyword “ovarian clear cell carcinoma” and filtered for interventional studies involving immunotherapeutic agents or combination therapies. Articles were selected based on their relevance to the pathogenesis, immune modulation, and emerging therapeutic approaches in OCCC.
3 Results
3.1 OCCC molecular signature
The most frequent genetic alterations observed in OCCC include mutations in the ARID1A, KRAS, PTEN, and PIK3CA genes (23). Additional oncogenic changes affecting the mitogen-activated protein kinase (MAPK) pathway have been reported, such as mutations in PPP2R1A, mutations and amplifications of ERBB2, and amplification of the MET proto-oncogene, which encodes the hepatocyte growth factor receptor (HGFR) (24). Recently, mutations in MUC4, MAGEE1, and ARID3A have been identified at notable frequencies, with MAGEE1 mutations correlating with poorer prognosis (25). Familial inheritance is rare in OCCC, which typically expresses wild-type p53 and exhibits a very low frequency of BRCA1 and BRCA2 mutations (26), while TERT promoter mutations occur more commonly (27).
OCCC is characterized by high expression levels of napsin A, hypoxia-inducible factor 1-alpha (HIF-1α) (28), glypican-3 (29), hepatocyte nuclear factor 1-beta (HNF-1β) (30), interleukin 6 (IL-6) (31), and MET (32), whereas estrogen receptor expression is generally absent (33, 34). Although cancer antigen 125 (CA125) levels are usually low in OCCC, elevated CA125 correlates with worse prognosis (35).
ARID1A, encoding the chromatin remodeler BAF250, is involved in transcriptional regulation, DNA synthesis, and cellular proliferation and differentiation. Mutations in ARID1A occur in approximately 50% of OCCC cases and represent an early event in tumorigenesis (36). ARID1A loss impairs interferon signaling, facilitating immune evasion (37), and is associated with increased expression of HDAC6, which promotes tumor cell invasion, migration, and poorer overall survival (38–40). The co-occurrence of ARID1A and PIK3CA mutations leads to hyperactivation of the phosphoinositide 3-kinase (PI3K) pathway via p110α, stimulating the PI3K/Akt/mammalian target of rapamycin (mTOR) cascade and enhancing cellular proliferation (33, 41–44).
Recent evidence implicates the PI3K/Akt/mTOR and extracellular signal-regulated kinase 1/2 (ERK1/2) pathways in OCCC chemoresistance. These pathways regulate progranulin (PGRN) overexpression (45) and induce HIF-1α expression, which promotes metabolic adaptations including increased glycogen accumulation in PIK3CA-mutated OCCC cells and contributes to chemoresistance (46). Furthermore, Akt/mTOR signaling upregulates vascular endothelial growth factor (VEGF), driving tumor angiogenesis critical for growth, invasion, and metastasis (47). The PI3K/Akt pathway also mediates resistance to ferroptosis, an iron-dependent oxidative stress-induced form of cell death, which is regulated by the Hippo signaling pathway (48). Notably, reduced Hippo pathway activity, particularly low nuclear expression of yes-associated protein 1 (YAP1) correlates with poor prognosis and resistance to ferroptosis inducer erastin. Suppression of zinc finger DHHC-type palmitoyltransferase 7 (ZDHHC7) activates YAP1, sensitizing OCCC cells to ferroptosis, suggesting that targeting ZDHHC7 to enhance YAP1-mediated ferroptosis represents a promising therapeutic approach (49).
Decreased PTEN expression or inactivation, known to promote gastric cancer via Hippo and PI3K/Akt pathway activation (50), may similarly contribute to OCCC pathogenesis. In OCCC, low PTEN levels lead to hyperactivation of the PI3K/Akt pathway and, when combined with ARID1A mutations, promote programmed death-ligand 1 (PD-L1) expression (51).
Combined ARID1A and PIK3CA mutations also elevate IL-6 expression, a known ARID1A-regulated gene (52). PIK3CA mutations drive sustained IL-6 production through PI3K/Akt hyperactivation in the context of ARID1A loss (36). IL-6 maintains JAK/STAT3 signaling, amplifying its own expression and promoting resistance to oxidative stress, tumor invasion, and chemoresistance (53–56). IL-6 additionally induces nuclear translocation and transcriptional activation of HIF-1α via STAT3, enhancing cisplatin resistance in ovarian cancer cells (57). HIF-1α, highly expressed in OCCC, contributes to glycogen accumulation, metabolic adaptation, and activation of IL-6 signaling (28, 46, 58). Through STAT3 activation, IL-6 induces VEGF expression, promoting angiogenesis and vascular permeability. Correspondingly, ARID1A mutations correlate with elevated VEGF levels, aggressive tumor phenotype, poor survival, and cisplatin resistance (59). VEGF also plays a role in tumor progression and exerts immunosuppressive effects in OCCC (60).
HNF-1β expression is characteristic of both endometriosis and OCCC, suggesting early differentiation of endometriosis into clear cell lineage. RNA interference studies show that HNF-1β is essential for OCCC cell survival, with its knockdown inducing apoptosis. HNF-1β promotes glycogen synthesis and aerobic glycolysis, contributing to the metabolic reprogramming that supports chemoresistance (61). Despite its importance, no targeted therapies against HNF-1β have yet been developed, highlighting the need for further investigation (62).
The HGFR signaling pathway is critical for cell growth, survival, and motility through activation of RAS-MAPK, PI3K/Akt/mTOR, and JAK/STAT3 pathways (63, 64). HGFR also functionally interacts with HIF-1α, regulating VEGF expression (65).
OCCC frequently exhibits mismatch repair deficiency (MMRd), resulting in accumulation of genetic abnormalities and microsatellite instability (MSI) (66, 67). MSI arises from mutations or methylation in mismatch repair genes such as MLH1, MSH2, and MSH6 (68). ARID1A mutations contribute to MMRd and MSI by disrupting protein interactions with MSH2 and promoting somatic MLH1 methylation (52, 69, 70). High MSI (MSI-H) occurs in 2–20% of ovarian cancers, predominantly in endometrioid carcinoma (EC) and OCCC (71). Diffuse intratumoral stromal inflammation has been reported as a histologic marker of MMRd in OCCC (72). OCCC tumors with MSI-H are highly immunogenic, exhibiting increased tumor-infiltrating lymphocytes (TILs) and elevated PD-L1 expression, which may predict enhanced responsiveness to immune checkpoint blockade (ICB) therapies (71, 73, 74).
In summary, the molecular landscape of OCCC converges on five major oncogenic pathways: PI3K/Akt/mTOR, HIF-1α/VEGF, HNF-1β, IL-6/STAT3, and HGFR. These interconnected signaling networks orchestrate tumor growth, angiogenesis, immune evasion, metabolic adaptation, and drug resistance, providing a strong rationale for the development of multi-targeted therapeutic strategies (Figure 1) (11, 75–77).
Figure 1. Gene mutations in OCCC and their association with the activation of pro-tumoral signaling pathways. PI3KCA/PTEN mutations induce high levels of PI3K/Akt/mTOR activation, which increases the expression and signaling of IL-6 and the expression of VEGF. VEGF, in turn, promotes angiogenesis and enhances the activity of Tregs and MDSCs, contributing to immunosuppression. IL-6, through its interaction with its receptor, activates STAT3, which enhances the nuclear translocation and transcriptional activity of HIF-1, resulting in chemoresistance and proliferation. Conversely, HIF-1 enhances the activation of STAT3. ARID1A mutations lead to increased levels of HDAC6. HDAC6 increases IL-10 expression, which, in turn, promotes the polarization of macrophages toward an M2 pro-tumoral phenotype, leading to IL-6 secretion and supporting immunosuppression. Concomitant mutations of ARID1A and PTEN promote the expression of immune checkpoints such as LAG-3 and PD-L1, contributing to T-cell anergy and the differentiation of Tregs.
3.2 The immune tumor microenvironment in OCCC
3.2.1 Anti-tumor immunity and the establishment of an immunosuppressive and pro-tumor TME
The TME constitutes a complex and dynamic milieu comprising cellular components, including cancer cells, endothelial cells, fibroblasts, granulocytes, lymphocytes, and macrophages, embedded in an altered extracellular matrix (ECM) (78). The ECM not only supports tumor architecture but also orchestrates cell-to-cell and cell-to-matrix signaling, and is enriched in inflammatory mediators, chemokines, and matrix-degrading enzymes, such as metalloproteinases, which drive matrix breakdown, neoplastic invasion, and angiogenic processes (79, 80). The immunomodulatory potential of the TME depends on its cellular composition, influencing both innate and adaptive immune responses (81). Among its immune components, TILs are critical for identifying and eradicating malignant cells via both innate defenses and antigen-specific mechanisms (82). Antigen-presenting cells (APCs) initiate adaptive responses by activating CD4+ T helper cells (Th1, Th2, Th17), regulatory T cells (Tregs), and cytotoxic T lymphocytes (CTLs) (75, 83, 84). Innate immunity relies on natural killer (NK) cells and macrophages. NK cells eliminate tumors with reduced major histocompatibility complex (MHC) expression (85), while M1-polarized macrophages produce pro-inflammatory cytokines (e.g., IL-6, IL-12, IFN-γ) and facilitate antigen presentation (86). However, the TME often impairs immune responses, recruiting Tregs, myeloid-derived suppressor cells (MDSCs), and tumor-associated macrophages (TAMs), which promote immunosuppression and tumor progression (87–89). Immune evasion is supported by the expression of immune checkpoints, including cytotoxic T-lymphocyte antigen 4 (CTLA-4), programmed cell death protein 1 (PD-1), and lymphocyte activation gene 3 (LAG-3), which inhibit T-cell activation (90–92). Hypoxia, a hallmark of the TME due to abnormal vasculature and high tumor cell proliferation, exacerbates immunosuppression by recruiting MDSCs, TAMs, and Tregs (93). HIFs, particularly HIF-1α, promote tumor cell survival, inflammation, and immune escape (94). Tumor-associated neutrophils and cancer-associated fibroblasts (CAFs) further reshape the TME, enhancing tumor growth, invasion, angiogenesis, and drug resistance (95, 96). In summary, the TME fosters tumor progression and immune evasion by altering immune cell phenotypes, creating hypoxic conditions, and facilitating intercellular communication, ultimately leading to metastatic potential and treatment resistance (97, 98).
3.2.2 Characteristics of the TME in OCCC
As for many types of cancer, the TME plays a crucial role in driving the aggressiveness and immune escape of ovarian cancer (99). Specifically, the TME in OCCC is characterized by a hypoxic environment that supports glycogen synthesis and accumulation (46). Chemoresistant subpopulations of OCCC cells exhibiting elevated HIF activity have been identified in areas enriched with CAFs that display a myofibroblastic phenotype (myCAFs). Indeed, myCAFs enhance OCCC chemoresistance and induce HIF-1α activity, mediated by platelet-derived growth factor (PDGF) signaling through PDGF receptors expressed by CAFs (100).
The OCCC TME displays a high-iron content feature, thought to derive from CD10-negative, endometriosis-derived mesenchymal stem cells (enMSCs) that support tumor growth by donating iron. These enMSCs overexpress iron-export proteins, increasing labile intracellular iron levels, which promote OCCC cell proliferation while shielding them from iron chelation therapies. However, this enhanced iron transfer simultaneously renders OCCC cells vulnerable to ferroptosis, identifying a potential therapeutic target for treatment (101).
Regarding immune escape, several studies have identified aberrant expression of various immune checkpoint genes in OCCC, including CTLA-4, PD-1, PD-L1, LAG-3, and T-cell immunoglobulin and mucin domain-containing protein 3 (TIM-3), positioning these as potential targets for ICB therapies. Collectively, these findings suggest that OCCC may be particularly responsive to ICB strategies (102). PD-L1 have been shown to be expressed in ovarian tumors and to represent negative prognostic markers. Moreover, PD-L1 promote immune evasion by inducing T-cell anergy or apoptosis, favoring tumor immune escape (103). In OCCC, PD-L1 expression is driven by ARID1A mutations (104, 105) and the hyperactivation of the PI3K/Akt pathway (51). The interaction of PD-L1 with PD-1 on T cells triggers inhibitory signals that suppress activated T lymphocytes, promote T-cell anergy and apoptosis, and ultimately lead to the activation and expansion of Tregs (106). VEGF expression plays an important role in the tumor progression of OCCC and, in addition to promoting angiogenesis, acts as an immunosuppressive agent by impairing T-cell function and APC function, and activating Tregs and MDSCs (60). The increased presence of Tregs within the OCCC TME has been associated with tumor progression and resistance across multiple stages of the disease (107). Moreover, frequent alteration of the PI3K/Akt/mTOR pathway observed in OCCC not only upregulates PD-L1 expression but also enhances the expression of LAG-3. This dual activation promotes resistance to cytotoxic T-cell-induced apoptosis, enhances Treg function, and enables evasion from death receptor-mediated signaling (108–111).
The expression of LAG-3 in TILs has been reported in OCCC and is associated with a poor prognosis (112). Furthermore, recent studies showed that the ARID1A6488delG mutation (113) induces M2 polarization of macrophages through IL-10, thus contributing to differentiation into TAMs and immunosuppressive conditions (40).
In summary, the OCCC TME is characterized by a hypoxic, iron-rich, and immunosuppressive profile, featuring the infiltration of Tregs and TAMs (Figure 2) (103, 114, 115).
Figure 2. Characteristics of the OCCC TME. The OCCC TME is highly immunosuppressive and pro-tumorigenic. This is characterized by hypoxia and angiogenesis driven by VEGF and HIF-1α, which promote tumor growth and chemoresistance. Endometriosis-derived mesenchymal stem cells (enMSCs) enrich the microenvironment with iron, sustaining OCCC proliferation but also conferring vulnerability to ferroptosis. Cancer-associated fibroblasts with a myofibroblastic phenotype (myCAFs) contribute to chemoresistance and enhance HIF-1α activity through PDGF signaling. The immune landscape includes regulatory T cells (Tregs) and M2-polarized macrophages, which suppress anti-tumor responses, alongside aberrant expression of immune checkpoints such as PD-1, PD-L1, and LAG-3 that promote T-cell anergy. Together, these features foster immune escape, therapeutic resistance, and disease progression.
3.3 Immune therapeutic strategies against OCCC
Despite the strong rationale for response to immunotherapy in OCCC, its clinical efficacy in EOC remains limited. Nevertheless, several ongoing clinical trials are exploring the use of immune checkpoint inhibitors (ICIs) in patients with advanced OCCC. Additionally, anti-angiogenic therapies have demonstrated potential in enhancing the efficacy of immunotherapy by modifying the TME and directly influencing immune effector cells (116).
In this regard, in newly diagnosed stage III or IV ovarian carcinoma, the IMagyn050/GOG 3015/ENGOT-OV39 phase III trial (NCT03038100) evaluated the addition of the PD-L1 inhibitor atezolizumab to standard platinum-based chemotherapy and bevacizumab. While no significant improvements were seen in PFS or OS (co-primary endpoints), post hoc subgroup analyses reported a numerical increase in PFS with the addition of atezolizumab in non-high grade serous histology, which included OCCC (117). The phase III study, NINJA (JapicCTI-153004), compared nivolumab (PD-1 inhibitor) with chemotherapy (gemcitabine or pegylated liposomal doxorubicin) in patients with platinum-resistant ovarian cancer. Although nivolumab was better tolerated and associated with a longer duration of response, it did not improve OS and showed inferior PFS compared with chemotherapy (118).
A phase II trial evaluated pembrolizumab in two cohorts of patients with recurrent ovarian cancer, stratified by treatment history and platinum-free intervals (NCT02674061). The overall response rate (ORR) was low—7.4% in cohort A (1–3 prior therapies) and 9.9% in cohort B (4–6 prior therapies)—with modest disease control rates (approximately 37%) in both groups. PD-L1 expression was associated with slightly higher responses (ORR 10%). PFS was 2.1 months, and OS was 17.6 months in cohort B (not reached in cohort A) (119).
The combination of nivolumab and ipilimumab (CTLA-4 inhibitor) in EOC yielded a higher ORR and slightly prolonged PFS than nivolumab alone, with manageable toxicity (NCT02498600). Notably, patients with OCCC demonstrated a fivefold higher ORR than other histologic subtypes, although the sample size was small (12% OCCC) (120).
Further supporting this trend, the results of the BrUOG 354 trial were absolutely promising and surprising. The BrUOG 354 trial (NCT03355976), a randomized two-stage, phase II study, evaluated nivolumab monotherapy versus nivolumab in combination with ipilimumab (nivolumab/ipilimumab) in patients with relapsed extra-renal CCC, including ovarian, endometrial, and cervical primaries. All participants had gynecologic tumors, with 36 (82%) diagnosed with OCCC. Patients had received a median of one prior line of therapy (range 1-7). The ORR was 14.3% (two partial responses) with nivolumab and 33% (four complete and six partial responses) with nivolumab/ipilimumab. Median PFS was 2.2 months (95% CI: 1.2–3.4) with nivolumab and 5.6 months (95% CI: 1.6–29.1) with nivolumab/ipilimumab. Median OS was 17.0 months (95% CI: 2.1–NR) with nivolumab and 24.6 months (95% CI: 5.9–NR) with nivolumab/ipilimumab. Grade 3 treatment-related adverse events occurred in 21% of patients on nivolumab and 47% of those on nivolumab/ipilimumab (including two grade 4 pancreatic enzyme elevations), with no treatment-related deaths reported. These results highlight the meaningful and durable clinical activity of nivolumab/ipilimumab, particularly in OCCC, and support its further evaluation in this historically chemotherapy-resistant population (121).
There are several ongoing clinical trials of anti-angiogenic therapy in combination with ICIs recruiting patients with OCCC. The combination of pembrolizumab (PD-1 inhibitor) with lenvatinib, an oral multikinase inhibitor that targets VEGF receptor, fibroblast growth factor receptor 1–3, PDGF receptor, RET, and KIT, has been evaluated in several gynecologic malignancies and is currently approved by the US Food and Drug Administration (FDA) for use in advanced, microsatellite stable, MMR proficient endometrial carcinoma (122). This combination has been shown to improve PFS and OS in endometrial cancer regardless of histologic subtypes. However, a post-hoc analysis suggests a specific clinical benefit in the clear cell histological subtype (123). In this regard, two phase II clinical trials on the combination of lenvatinib plus pembrolizumab are currently recruiting patients with recurrent or persistent OCCC who have received at least one prior line of platinum-based chemotherapy. The LARA phase II trial (Singapore and South Korea, NCT04699071) evaluates the combination of pembrolizumab and lenvatinib in recurrent clear cell gynecological cancer. The preliminary efficacy reported achieving an objective response in four out of 15 patients in the first 24 weeks (ORR at 24 weeks, 26.7%; 95% CI: 7.8–55.1). The median PFS was 12 weeks (95% CI: 5.4–24.4); PFS at 12 and 24 weeks was achieved in 46.7% (95% CI: 21.2–68.7) and 33.3% (95% CI: 12.2–56.4) of patients, respectively (124).
Similarly, the NCT05296512 trial is recruiting patients with recurrent or persistent OCCC in the USA to undergo an experimental combination of pembrolizumab and lenvatinib (125, 126). Interestingly, McNamara and colleagues reported the case of a patient with recurrent treatment-resistant OCCC with ARID1A/PIK3CA mutations after failing standard and experimental treatments, who had a partial and durable response with pembrolizumab and lenvatinib over 7 months of treatment approved on a compassionate basis (127). Regarding the use of immunotherapy, two recent single-arm, multicenter, phase II trials reported interesting data at the European Society for Medical Oncology (ESMO) 2022 congress. The British PEACOCC (NCT03425565) study enrolled 49 recurrent CCC, of whom 85.4% were OCCC. The study exhibited the promising efficacy of pembrolizumab monotherapy with a 12-week PFS rate of 43.8% (95% CI: 31.5–56.6) (128).
Furthermore, the Chinese INOVA (NCT04735861) study investigated the potential benefit of combining sintilimab (PD-1 inhibitor) and bevacizumab for recurrent or persistent OCCC (129). Preliminary results on 23 patients (of whom 18 were platinum-resistant and 20 with radiological evaluation) reported an ORR of 40% (one complete and seven partial responses; 95% CI: 19.1–63.9) and a disease control rate of 75% (eight partial responses, seven stable diseases; 95% CI: 50.9–91.3%) (130).
Notably, MITO 27 (NCT04375956), a prospective non-randomized phase II study, evaluates the use of pembrolizumab only for patients with a combined positive score >1 in recurrent, platinum-resistant OC, including clear cell histology (131).
The MOCCA trial (NCT03405454) testing durvalumab, an anti-PD-L1 monoclonal antibody, versus standard chemotherapy in patients with recurrent OCCC showed no significant difference in PFS, ORR, or clinical benefit rate. However, correlative translational analyses to elucidate potential predictive biomarkers of response and resistance are ongoing (132).
Finally, BOUQUET (NCT04931342) is a phase II, open-label, non-randomized, multicenter, platform study evaluating biomarker-driven treatments in patients with persistent or recurrent ovarian, fallopian tube, or primary peritoneal tumors of rare epithelial histology, including OCCC (133). The treatment arm to which eligible patients are assigned will be determined by the biomarker profile of their tumor. Recently, the first interim results have been reported from the cobimetinib arm, a mitogen-activated extracellular signal-regulated kinase 1 (MEK1) inhibitor and from the role of combination of atezolizumab (anti-PD-L1) plus bevacizumab (anti-VEGF) arm. Specifically, as of the clinical cut-off date, five patients with OCCC had received cobimetinib, and three patients with OCCC had received the combination with bevacizumab and atezolizumab. All patients were heavily pretreated. Confirmed objective response rates were 16% with cobimetinib and 14% with atezolizumab plus bevacizumab. This trial continues to evaluate biomarker-driven therapies for rare epithelial ovarian cancer (134).
Recently, a press release from Merck announced that the phase 3 KEYNOTE-B96/ENGOT-ov65 trial (NCT05116189) assessing pembrolizumab plus paclitaxel with or without bevacizumab reached the primary endpoint of PFS among patients with platinum-resistant ovarian cancer across the all-comer and PD-L1-positive populations.
Table 1 summarizes the findings of the clinical trials presented.
Table 1. Clinical trials with immune checkpoint inhibitors enrolling patients with advanced OCCC.
3.4 Possible new therapeutic strategies and future perspectives in OCCC treatment
Given the complexity of the OCCC TME, therapeutic strategies that combine ICIs with agents targeting key molecules implicated in tumor aggressiveness such as VEGF, HIF-1α, IL-6, IL-10, PI3K, and HDAC6 show considerable promise (Figure 3).
Figure 3. Potential therapeutic strategies targeting the OCCC TME. The diagram illustrates the multifaceted effects of combining targeted therapies counteracting key tumor-promoting pathways (IL-6/IL-6R/STAT3, HIF-1α, VEGF/VEGFR, PD-1/PD-L1, LAG3, and HDAC) on tumor growth, immune modulation, angiogenesis, and chemoresistance. Checkpoint inhibitors (anti-PD-1, anti-PD-L1, and anti-LAG-3) restore T-cell activation and effector function, while anti-VEGF and anti-VEGFR therapies inhibit angiogenesis and tumor vascularization. Inhibition of the IL-6 signaling pathway with anti-IL-6, anti-IL-6R, or anti-STAT3 antibodies, alone or in combination with anti-HIF-1α, leads to reduced angiogenesis, invasion, and chemoresistance. Additional strategies such as anti-HDAC agents might further enhance T-cell activity and reduce immunosuppression macrophage polarization. The combined effects of these therapeutic approaches potentially result in a more immunostimulatory tumor microenvironment and attenuation of OCCC progression.
Notably, an in vivo study employing animal models demonstrated that combining HDAC6 inhibition via ACY1215 with ICIs constitutes a potential therapeutic approach for ARID1A-mutated OCCC, effectively limiting tumor progression through a cytotoxic T-cell-dependent mechanism (139).
EZN-2208, an inhibitor of HIF-1α, has displayed anti-tumor activity both as monotherapy and in combination with bevacizumab in phase I clinical trials involving refractory solid tumors (140, 141). Additionally, an in vitro study revealed that PX-478, another HIF-1α inhibitor, enhanced T cell-mediated tumor cell killing when combined with ICIs in non-small cell lung cancer models (142). Beyond ICIs, HIF-1α inhibitors may also be combined with anti-angiogenic agents, representing a promising strategy in OCCC. Considering the interplay between HIF-1α and IL-6, dual inhibition targeting IL-6, its receptor, or downstream STAT3 signaling alongside HIF-1α may provide an effective therapeutic avenue.
Co-inhibition of PD-1 and CTLA-4 has demonstrated antitumor efficacy in OCCC patients; however, this approach is often limited by severe immune-related adverse events (120, 143). Given these limitations, a randomized phase III trial in melanoma showed that combined inhibition of PD-1 and LAG-3 resulted in improved clinical outcomes (78), suggesting that targeting PD-1 and LAG-3, rather than PD-1 and CTLA-4, could be a safer and potentially more effective strategy in OCCC. Currently, only a few early-phase clinical studies (phases 1 and 2) have investigated anti-LAG-3 monoclonal antibodies (mAbs) as monotherapy or in combination with other ICIs such as anti-PD-1 and anti-CTLA-4 in advanced solid tumors, including ovarian cancer. Despite strong scientific rationale, no clinical trials specifically evaluating anti-LAG-3 therapy in OCCC have been reported to date.
Moreover, inhibition of IL-6 signaling through the IL-6 receptor alpha (IL-6Rα) inhibitor tocilizumab has been shown to enhance the efficacy of cytotoxic chemotherapy by promoting cytotoxic T lymphocyte (CTL)-mediated antitumor responses, concurrently downregulating PD-L1 expression and potentially augmenting responses to ICIs (144).
IL-10 blockade—achieved using soluble IL-10 receptors (145), peptide-based IL-10 receptor antagonists (146), or oligonucleotide-based inhibitors (147)—may further potentiate antitumor immunity in OCCC by augmenting T-cell responses and reprogramming tumor-associated macrophages (TAMs). These immunomodulatory effects could be synergistically enhanced when combined with IL-6 and VEGF inhibition or ICIs.
Inhibition of the PI3K/Akt/mTOR and ERK1/2 signaling pathways has been shown to reduce progranulin (PGRN) expression in ovarian cancer cells, suggesting a potential strategy to overcome chemoresistance in OCCC. Alpelisib (BYL719), the first oral isoform-selective PI3K inhibitor targeting the p110α isoform of wild-type PI3Kα, has received FDA and EMA approval for metastatic breast cancer treatment (148). Alpelisib has also been employed in advanced gynecologic malignancies harboring PIK3CA mutations, including ovarian cancer. While the most notable clinical benefit has been observed in endometrial cancer patients (149), including a documented case of PIK3CA-mutated endometrial cancer achieving a clinically meaningful response (150), in ovarian cancer cohorts, patients with OCCC demonstrated a disease control rate of 50% (2 stable disease, 1 partial response) (149).
Therefore, it is crucial that translational research focuses on finding valid predictive biomarkers of response to new personalized therapies in addition to the potential expression of PD-L1 and the critical importance of designing clinical trials specifically dedicated to the OCCC histotype.
4 Conclusion
OCCC represents a challenging subtype of EOC, owing to its distinct molecular features, limited response to conventional therapies, a poor prognosis and highly immunosuppressive TME. Frequent genetic and molecular alterations in OCCC, including ARID1A and PIK3CA mutations, lead to hyperactivation of the PI3K/Akt/mTOR pathway and the overexpression of IL-6, IL-10, HDAC6, VEGF, and HIF-1α, collectively driving its aggressive behavior, chemoresistance, and immune evasion.
The immunosuppressive TME of OCCC, characterized by a high infiltration of Tregs, TAMs, and elevated levels of immune checkpoint molecules such as PD-L1 and LAG-3, could be an attractive target for the immune therapeutic intervention.
These features underline the complexity of managing OCCC and highlight the urgent need for innovative therapeutic approaches, including immunotherapy.
Despite increasing understanding of OCCC pathophysiology, current therapeutic strategies, including ICIs and anti-angiogenic agents, have shown limited clinical efficacy in this cancer type. Nevertheless, emerging evidence from ongoing clinical trials suggests potential benefits from combinatorial therapies targeting multiple pathways. For instance, the combination of pembrolizumab with lenvatinib or VEGF inhibitors has demonstrated promising activity in subsets of OCCC patients, underscoring the importance of multi-targeted approaches. Similarly, preclinical studies suggest that inhibiting key molecules such as IL-6, HIF-1α, HDAC6, or IL-10, in combination with ICIs, could overcome resistance mechanisms and enhance treatment efficacy. Future therapeutic strategies should focus on leveraging the intricate interplay between the genetic and immunological features of OCCC. Targeting ARID1A-mutated tumors through specific inhibitors of HDAC6 or IL-6 signaling could reprogram the immunosuppressive TME and restore T-cell-mediated cytotoxicity. Additionally, continued exploration of innovative combinations, such as dual ICB (e.g., PD-1 and LAG-3 inhibition) may further expand the therapeutic armamentarium for this malignancy.
In conclusion, while OCCC remains a formidable clinical challenge, advances in molecular and immunologic research offer hope for more effective and durable therapeutic options. Future studies should prioritize the integration of targeted therapies with immunomodulatory agents to address the multifaceted nature of OCCC, ultimately improving outcomes for patients with this rare and aggressive cancer.
Author contributions
AP: Data curation, Writing – review & editing, Conceptualization, Writing – original draft. SC: Writing – review & editing. JV: Writing – review & editing. CP: Writing – review & editing. RD: Writing – review & editing. SR: Writing – review & editing. RT: Writing – review & editing. MD: Writing – review & editing. LL: Writing – review & editing. GC: Writing – review & editing. ML: Writing – review & editing. EP: Writing – review & editing. MP: Writing – review & editing. ES: Writing – review & editing.. SS: Writing – review & editing. FF: Writing – review & editing. SVS: Writing – review & editing. DC: Writing – review & editing. SP: Writing – review & editing, Writing – original draft, Conceptualization, Data curation.
Funding
The author(s) declare financial support was received for the research and/or publication of this article. The study was partially supported by Ministry of Health Ricerca Corrente L4/81_25 to SP.
Acknowledgments
The authors acknowledge Lara Vecchi, Valentina Attanasio, and Aashni Shah (Polistudium Srl, Milan, Italy) for medical writing, editorial assistance, and English editing, and Massimiliano Pianta (Polistudium Srl, Milan, Italy) for graphic support.
Conflict of interest
SP received honoraria from MSD, Roche, GSK, Novartis, and PharmaMar; research funding from MSD, AZ, Pfizer, and GSK. CP received honoraria from MSD, AZ, GSK, and EISAI. MD received honoraria from MSD, IPSEN, and BMS. SR received honoraria from MSD, AZ, J&J, Astellas, Ipsen, Recordati, Accord, Novartis, and Pfizer.
The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
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References
1. Siegel RL, Miller KD, and Jemal A. Cancer statistics, 2019. CA Cancer J Clin. (2019) 69:7–34. doi: 10.3322/caac.21551
2. Prat J, D'Angelo E, and Espinosa I. Ovarian carcinomas: at least five different diseases with distinct histological features and molecular genetics. Hum Pathol. (2018) 80:11–27. doi: 10.1016/j.humpath.2018.06.018
3. Rodrigues S, Braga M, Félix A, and Cunha TM. Clear cell carcinoma of the ovary: Clues for radiologists to perform a correct diagnosis. Curr Probl Diagn Radiol. (2024) 53:271–9. doi: 10.1067/j.cpradiol.2023.10.003
4. Suda K, Cruz Diaz LA, Yoshihara K, Nakaoka H, Yachida N, Motoyama T, et al. Clonal lineage from normal endometrium to ovarian clear cell carcinoma through ovarian endometriosis. Cancer Sci. (2020) 111:3000–9. doi: 10.1111/cas.14507
5. Saavalainen L, Lassus H, But A, Tiitinen A, Härkki P, Gissler M, et al. Risk of gynecologic cancer according to the type of endometriosis. Obstet Gynecol. (2018) 131:1095–102. doi: 10.1097/AOG.0000000000002624
6. Pearce CL, Templeman C, Rossing MA, Lee A, Near AM, Webb PM, et al. Association between endometriosis and risk of histological subtypes of ovarian cancer: a pooled analysis of case-control studies. Lancet Oncol. (2012) 13:385–94. doi: 10.1016/S1470-2045(11)70404-1
7. Worley MJ, Welch WR, Berkowitz RS, and Ng SW. Endometriosis-associated ovarian cancer: a review of pathogenesis. Int J Mol Sci. (2013) 14:5367–79. doi: 10.3390/ijms14035367
8. World Health Organization. Tumours of the ovary and peritoneum. In: Tavassoli FA and Devilee P, editors. Pathology and genetics: Tumours of the breast and female genital organs, 3rd ed. IARC Press, Lyon (France (2003). p. 113–216.
9. Longacre TA, Wells M, Bell DA, Malpica A, Prat J, and Ronnett BM. Tumours of the ovary. In: Kurman RJ, Carcangiu ML, Herrington S, and Young RH, editors. WHO classification of tumours of female reproductive organs, 4th ed. IARC Press, Lyon (2014). p. 11–86.
10. Winter WE 3rd, Maxwell GL, Tian C, Carlson JW, Ozols RF, Rose PG, et al. Prognostic factors for stage III epithelial ovarian cancer: a Gynecologic Oncology Group Study. J Clin Oncol. (2007) 25:3621–7. doi: 10.1200/JCO.2006.10.2517
11. Liu Z, Jing C, and Kong F. From clinical management to personalized medicine: novel therapeutic approaches for ovarian clear cell cancer. J Ovarian Res. (2024) 17:39. doi: 10.1186/s13048-024-01359-7
12. Anglesio MS, Carey MS, Köbel M, Mackay H, and Huntsman DG. Vancouver Ovarian Clear Cell Symposium Speakers. Clear cell carcinoma of the ovary: a report from the first Ovarian Clear Cell Symposium, June 24th, 2010. Gynecol Oncol. (2011) 121:407–15. doi: 10.1016/j.ygyno.2011.01.005
13. Jin Y, Li Y, and Pan L. The target therapy of ovarian clear cell carcinoma. Onco Targets Ther. (2014) 7:1647–52. doi: 10.2147/OTT.S49993
14. Duska LR, Garrett L, Henretta M, Ferriss JS, Lee L, and Horowitz N. When 'never-events' occur despite adherence to clinical guidelines: the case of venous thromboembolism in clear cell cancer of the ovary compared with other epithelial histologic subtypes. Gynecol Oncol. (2010) 116:374–7. doi: 10.1016/j.ygyno.2009.10.069
15. Matsuo K, Hasegawa K, Yoshino K, Murakami R, Hisamatsu T, Stone RL, et al. Venous thromboembolism, interleukin-6 and survival outcomes in patients with advanced ovarian clear cell carcinoma. Eur J Cancer. (2015) 51:1978–88. doi: 10.1016/j.ejca.2015.07.012
16. Diaz ES, Walts AE, Karlan BY, and Walsh CS. Venous thromboembolism during primary treatment of ovarian clear cell carcinoma is associated with decreased survival. Gynecol Oncol. (2013) 131:541–5. doi: 10.1016/j.ygyno.2013.09.005
17. Matsuura Y, Robertson G, Marsden DE, Kim SN, Gebski V, and Hacker NF. Thromboembolic complications in patients with clear cell carcinoma of the ovary. Gynecol Oncol. (2007) 104:406–10. doi: 10.1016/j.ygyno.2006.08.026
18. Chan JK, Teoh D, Hu JM, Shin JY, Osann K, and Kapp DS. Do clear cell ovarian carcinomas have poorer prognosis compared to other epithelial cell types? A study of 1411 clear cell ovarian cancers. Gynecol Oncol. (2008) 109:370–6. doi: 10.1016/j.ygyno.2008.02.006
19. Itamochi H, Kigawa J, and Terakawa N. Mechanisms of chemoresistance and poor prognosis in ovarian clear cell carcinoma. Cancer Sci. (2008) 99:653–8. doi: 10.1111/j.1349-7006.2008.00747.x
20. Marks EI, Brown VS, and Dizon DS. Genomic and molecular abnormalities in gynecologic clear cell carcinoma. Am J Clin Oncol. (2020) 43:139–45. doi: 10.1097/COC.0000000000000641
21. Tang H, Liu Y, Wang X, Guan L, Chen W, Jiang H, et al. Clear cell carcinoma of the ovary: Clinicopathologic features and outcomes in a Chinese cohort. Med (Baltimore). (2018) 97:e10881. doi: 10.1097/MD.0000000000010881
22. Lee HY, Hong JH, Byun JH, Kim HJ, Baek SK, Kim JY, et al. Clinical characteristics of clear cell ovarian cancer: a retrospective multicenter experience of 308 patients in South Korea. Cancer Res Treat. (2020) 52:277–83. doi: 10.4143/crt.2019.292
23. Tan DS and Kaye S. Ovarian clear cell adenocarcinoma: a continuing enigma. J Clin Pathol. (2007) 60:355–60. doi: 10.1136/jcp.2006.040030
24. Iida Y, Okamoto A, Hollis RL, Gourley C, and Herrington CS. Clear cell carcinoma of the ovary: a clinical and molecular perspective. Int J Gynecol Cancer. (2021) 31:605–16. doi: 10.1136/ijgc-2020-001656
25. Yang Q, Zhang C, Ren Y, Yi H, Luo T, Xing F, et al. Genomic characterization of Chinese ovarian clear cell carcinoma identifies driver genes by whole exome sequencing. Neoplasia. (2020) 22:399–430. doi: 10.1016/j.neo.2020.06.002
26. Enomoto T, Aoki D, Hattori K, Jinushi M, Kigawa J, Takeshima N, et al. The first Japanese nationwide multicenter study of BRCA mutation testing in ovarian cancer: CHARacterizing the cross-sectionaL approach to Ovarian cancer geneTic TEsting of BRCA (CHARLOTTE). Int J Gynecol Cancer. (2019) 29:1043–9. doi: 10.1136/ijgc-2019-000384
27. Kobayashi T, Nishikimi K, Mitsuhashi A, Piao H, Matsuoka A, Otsuka S, et al. Suppressor-type TERT mutations associated with recurrence in ovarian clear cell carcinoma. Genes Chromosomes Cancer. (2023) 62:471–6. doi: 10.1002/gcc.23129
28. Lee S, Garner EI, Welch WR, Berkowitz RS, and Mok SC. Over-expression of hypoxia-inducible factor 1 alpha in ovarian clear cell carcinoma. Gynecol Oncol. (2007) 106:311–7. doi: 10.1016/j.ygyno.2007.03.041
29. Stadlmann S, Gueth U, Baumhoer D, Moch H, Terracciano L, and Singer G. Glypican-3 expression in primary and recurrent ovarian carcinomas. Int J Gynecol Pathol. (2007) 26:341–4. doi: 10.1097/pgp.0b013e31802d692c
30. Kato N, Sasou S, and Motoyama T. Expression of hepatocyte nuclear factor-1beta (HNF-1beta) in clear cell tumors and endometriosis of the ovary. Mod Pathol. (2006) 19:83–9. doi: 10.1038/modpathol.3800492
31. Seki T, Yanaihara N, Shapiro JS, Saito M, Tabata J, Yokomizo R, et al. Interleukin-6 as an enhancer of anti-angiogenic therapy for ovarian clear cell carcinoma. Sci Rep. (2021) 11:7689. doi: 10.1038/s41598-021-86913-9
32. Yamashita Y, Akatsuka S, Shinjo K, Yatabe Y, Kobayashi H, Seko H, et al. Met is the most frequently amplified gene in endometriosis-associated ovarian clear cell adenocarcinoma and correlates with worsened prognosis. PloS One. (2013) 8:e57724. doi: 10.1371/journal.pone.0057724
33. Mabuchi S, Sugiyama T, and Kimura T. Clear cell carcinoma of the ovary: molecular insights and future therapeutic perspectives. J Gynecol Oncol. (2016) 27:e31. doi: 10.3802/jgo.2016.27.e31
34. Köbel M, Piskorz AM, Lee S, Lui S, LePage C, Marass F, et al. Optimized p53 immunohistochemistry is an accurate predictor of TP53 mutation in ovarian carcinoma. J Pathol Clin Res. (2016) 2:247–58. doi: 10.1002/cjp2.53
35. Yoshida K, Yoshikawa N, Shirakawa A, Niimi K, Suzuki S, Kajiyama H, et al. Prognostic value of neutrophil-to-lymphocyte ratio in early-stage ovarian clear-cell carcinoma. J Gynecol Oncol. (2019) 30:e85. doi: 10.3802/jgo.2019.30.e85
36. Chandler RL, Damrauer JS, Raab JR, Schisler JC, Wilkerson MD, Didion JP, et al. Coexistent ARID1A-PIK3CA mutations promote ovarian clear-cell tumorigenesis through pro-tumorigenic inflammatory cytokine signalling. Nat Commun. (2015) 6:6118. doi: 10.1038/ncomms7118
37. Li J, Wang W, Zhang Y, Cieślik M, Guo J, Tan M, et al. Epigenetic driver mutations in ARID1A shape cancer immune phenotype and immunotherapy. J Clin Invest. (2020) 130:2712–26. doi: 10.1172/JCI134402
38. Yano M, Katoh T, Miyazawa M, Ogane N, Miwa M, Hasegawa K, et al. Clinicopathological correlation of ARID1A status with HDAC6 and its related factors in ovarian clear cell carcinoma. Sci Rep. (2019) 9:2397. doi: 10.1038/s41598-019-38653-0
39. Pham TQ, Robinson K, Xu L, Pavlova MN, Skapek SX, and Chen EY. HDAC6 promotes growth, migration/invasion, and self-renewal of rhabdomyosarcoma. Oncogene. (2021) 40:578–91. doi: 10.1038/s41388-020-01550-2
40. Hsieh TH, Hsu CY, Wu CW, Wang SH, Yeh CH, Cheng KH, et al. Vorinostat decrease M2 macrophage polarization through ARID1A6488delG/HDAC6/IL-10 signaling pathway in endometriosis-associated ovarian carcinoma. BioMed Pharmacother. (2023) 161:114500. doi: 10.1016/j.biopha.2023.114500
41. Yamamoto S, Tsuda H, Takano M, Tamai S, and Matsubara O. Loss of ARID1A protein expression occurs as an early event in ovarian clear-cell carcinoma development and frequently coexists with PIK3CA mutations. Mod Pathol. (2012) 25:615–24. doi: 10.1038/modpathol.2011.189
42. Madsen RR, Vanhaesebroeck B, and Semple RK. Cancer-associated PIK3CA mutations in overgrowth disorders. Trends Mol Med. (2018) 24:856–70. doi: 10.1016/j.molmed.2018.08.003
43. Yagyu T, Tsuji Y, Haruta S, Kitanaka T, Yamada Y, Kawaguchi R, et al. Activation of mammalian target of rapamycin in postmenopausal ovarian endometriosis. Int J Gynecol Cancer. (2006) 16:1545–51. doi: 10.1111/j.1525-1438.2006.00625.x
44. Kuo KT, Mao TL, Jones S, Veras E, Ayhan A, Wang TL, et al. Frequent activating mutations of PIK3CA in ovarian clear cell carcinoma. Am J Pathol. (2009) 174:1597–601. doi: 10.2353/ajpath.2009.081000
45. Perez-Juarez CE, Arechavaleta-Velasco F, Zeferino-Toquero M, Alvarez-Arellano L, Estrada-Moscoso I, and Diaz-Cueto L. Inhibition of PI3K/AKT/mTOR and MAPK signaling pathways decreases progranulin expression in ovarian clear cell carcinoma (OCCC) cell line: a potential biomarker for therapy response to signaling pathway inhibitors. Med Oncol. (2019) 37:4. doi: 10.1007/s12032-019-1326-5
46. Iida Y, Aoki K, Asakura T, Ueda K, Yanaihara N, Takakura S, et al. Hypoxia promotes glycogen synthesis and accumulation in human ovarian clear cell carcinoma. Int J Oncol. (2012) 40:2122–30. doi: 10.3892/ijo.2012.1406
47. Wang S, Lu J, You Q, Huang H, Chen Y, and Liu K. The mTOR/AP-1/VEGF signaling pathway regulates vascular endothelial cell growth. Oncotarget. (2016) 7:53269–76. doi: 10.18632/oncotarget.10756
48. Su H, Peng C, and Liu Y. Regulation of ferroptosis by PI3K/Akt signaling pathway: a promising therapeutic axis in cancer. Front Cell Dev Biol. (2024) 12:1372330. doi: 10.3389/fcell.2024.1372330
49. Furutake Y, Yamaguchi K, Yamanoi K, Kitamura S, Takamatsu S, Taki M, et al. YAP1 suppression by ZDHHC7 is associated with ferroptosis resistance and poor prognosis in ovarian clear cell carcinoma. Mol Cancer Ther. (2024) 23:1652–65. doi: 10.1158/1535-7163.MCT-24-0145
50. Xu W, Yang Z, Xie C, Zhu Y, Shu X, Zhang Z, et al. PTEN lipid phosphatase inactivation links the Hippo and PI3K/Akt pathways to induce gastric tumorigenesis. J Exp Clin Cancer Res. (2018) 37:198. doi: 10.1186/s13046-018-0795-2
51. Chen J, Jiang CC, Jin L, and Zhang XD. Regulation of PD-L1: a novel role of pro-survival signalling in cancer. Ann Oncol. (2016) 27:409–16. doi: 10.1093/annonc/mdv615
52. Shen J, Ju Z, Zhao W, Wang L, Peng Y, Ge Z, et al. ARID1A deficiency promotes mutability and potentiates therapeutic antitumor immunity unleashed by immune checkpoint blockade. Nat Med. (2018) 24:556–62. doi: 10.1038/s41591-018-0012-z
53. Chang Q, Daly L, and Bromberg J. The IL-6 feed-forward loop: a driver of tumorigenesis. Semin Immunol. (2014) 26:48–53. doi: 10.1016/j.smim.2014.01.007
54. Yanaihara N, Hirata Y, Yamaguchi N, Noguchi Y, Saito M, Nagata C, et al. Antitumor effects of interleukin-6 (IL-6)/interleukin-6 receptor (IL-6R) signaling pathway inhibition in clear cell carcinoma of the ovary. Mol Carcinog. (2016) 55:832–41. doi: 10.1002/mc.22325
55. Kawabata A, Yanaihara N, Nagata C, Saito M, Noguchi D, Takenaka M, et al. Prognostic impact of interleukin-6 expression in stage I ovarian clear cell carcinoma. Gynecol Oncol. (2017) 146:609–14. doi: 10.1016/j.ygyno.2017.06.027
56. Mehner C, Miller E, Hockla A, Coban M, Weroha SJ, Radisky DC, et al. Targeting an autocrine IL-6-SPINK1 signaling axis to suppress metastatic spread in ovarian clear cell carcinoma. Oncogene. (2020) 39:6606–18. doi: 10.1038/s41388-020-01451-4
57. Xu S, Yu C, Ma X, Li Y, Shen Y, Chen Y, et al. IL-6 promotes nuclear translocation of HIF-1α to aggravate chemoresistance of ovarian cancer cells. Eur J Pharmacol. (2021) 894:173817. doi: 10.1016/j.ejphar.2020.173817
58. Yanaihara N, Anglesio MS, Ochiai K, Hirata Y, Saito M, Nagata C, et al. Cytokine gene expression signature in ovarian clear cell carcinoma. Int J Oncol. (2012) 41:1094–100. doi: 10.3892/ijo.2012.1533
59. Mabuchi S, Kawase C, Altomare DA, Morishige K, Hayashi M, Sawada K, et al. Vascular endothelial growth factor is a promising therapeutic target for the treatment of clear cell carcinoma of the ovary. Mol Cancer Ther. (2010) 9:2411–22. doi: 10.1158/1535-7163.MCT-10-0169
60. Bourhis M, Palle J, Galy-Fauroux I, and Terme M. Direct and indirect modulation of T cells by VEGF-A counteracted by anti-angiogenic treatment. Front Immunol. (2021) 12:616837. doi: 10.3389/fimmu.2021.616837
61. Amano Y, Mandai M, Yamaguchi K, Matsumura N, Kharma B, Baba T, et al. Metabolic alterations caused by HNF1β expression in ovarian clear cell carcinoma contribute to cell survival. Oncotarget. (2015) 6:26002–17. doi: 10.18632/oncotarget.4692
62. Matsuzaki S, Yoshino K, Ueda Y, Matsuzaki S, Kakuda M, Okazawa A, et al. Potential targets for ovarian clear cell carcinoma: a review of updates and future perspectives. Cancer Cell Int. (2015) 15:117. doi: 10.1186/s12935-015-0267-0
63. Hervieu A and Kermorgant S. The role of PI3K in Met driven cancer: a recap. Front Mol Biosci. (2018) 5:86. doi: 10.3389/fmolb.2018.00086
64. Furge KA, Kiewlich D, Le P, Vo MN, Faure M, Howlett AR, et al. Suppression of Ras-mediated tumorigenicity and metastasis through inhibition of the Met receptor tyrosine kinase. Proc Natl Acad Sci USA. (2001) 98:10722–7. doi: 10.1073/pnas.191067898
65. Smyth EC, Sclafani F, and Cunningham D. Emerging molecular targets in oncology: clinical potential of MET/hepatocyte growth-factor inhibitors. Onco Targets Ther. (2014) 7:1001–14. doi: 10.2147/OTT.S44941
66. Zhao P, Li L, Jiang X, and Li Q. Mismatch repair deficiency/microsatellite instability-high as a predictor for anti-PD-1/PD-L1 immunotherapy efficacy. J Hematol Oncol. (2019) 12:54. doi: 10.1186/s13045-019-0738-1
67. Nojadeh JN, Behrouz Sharif S, and Sakhinia E. Microsatellite instability in colorectal cancer. EXCLI J. (2018) 17:159–68. doi: 10.17179/excli2017-948
68. Pal T, Akbari MR, Sun P, Lee JH, Fulp J, Thompson Z, et al. Frequency of mutations in mismatch repair genes in a population-based study of women with ovarian cancer. Br J Cancer. (2012) 107:1783–90. doi: 10.1038/bjc.2012.452
69. Durán M, Faull I, Lastra E, Laes JF, Rodrigo AB, and Sánchez-Escribano R. ARID1A genomic alterations driving microsatellite instability through somatic MLH1 methylation with response to immunotherapy in metastatic lung adenocarcinoma: a case report. J Med Case Rep. (2021) 15:89. doi: 10.1186/s13256-020-02589-1
70. Ge H, Xiao Y, Qin G, Gu Y, Cai X, Jiang W, et al. Mismatch repair deficiency is associated with specific morphologic features and frequent loss of ARID1A expression in ovarian clear cell carcinoma. Diagn Pathol. (2021) 16:12. doi: 10.1186/s13000-021-01071-w
71. Howitt BE, Strickland KC, Sholl LM, Rodig S, Ritterhouse LL, Chowdhury D, et al. Clear cell ovarian cancers with microsatellite instability: a unique subset of ovarian cancers with increased tumor-infiltrating lymphocytes and PD-1/PD-L1 expression. Oncoimmunology. (2017) 6:e1277308. doi: 10.1080/2162402X.2016.1277308
72. Bennett JA, Morales-Oyarvide V, Campbell S, Longacre TA, and Oliva E. Mismatch repair protein expression in clear cell carcinoma of the ovary: incidence and morphologic associations in 109 cases. Am J Surg Pathol. (2016) 40:656–63. doi: 10.1097/PAS.0000000000000602
73. Lin SY, Hang JF, Lin YY, Lai CR, Ho HL, and Chou TY. Diffuse intratumoral stromal inflammation in ovarian clear cell carcinoma is associated with loss of mismatch repair protein and high PD-L1 expression. Int J Gynecol Pathol. (2021) 40:148–55. doi: 10.1097/PGP.0000000000000682
74. Le DT, Durham JN, Smith KN, Wang H, Bartlett BR, Aulakh LK, et al. Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade. Science. (2017) 357:409–13. doi: 10.1126/science.aan6733
75. Zhao Q, Jiang Y, Xiang S, Kaboli PJ, Shen J, Zhao Y, et al. Engineered TCR-T cell immunotherapy in anticancer precision medicine: pros and cons. Front Immunol. (2021) 30:658753. doi: 10.3389/fimmu.2021.658753
76. Jin J, Wu X, Yin J, Li M, Shen J, Li J, et al. Identification of genetic mutations in cancer: challenge and opportunity in the new era of targeted therapy. Front Oncol. (2019) 9:263. doi: 10.3389/fonc.2019.00263
77. Xiang S, Li J, Shen J, Zhao Y, Wu X, and Li M. e identification of prognostic genes in the tumor microenvironment of hepatocellular carcinoma. Front Immunol. (2021) 12:653836. doi: 10.3389/fimmu.2021.653836
78. Tawbi HA, SChadendorf D, Lipson EJ, Ascierto PA, Matamala L, Castillo Gutiérrez E, et al. Relatlimab and nivolumab versus nivolumab in untreated advanced melanoma. N Engl J Med. (2022) 386:24–34. doi: 10.1056/NEJMoa2109970
79. Erdogan B and Webb DJ. Cancer-associated fibroblasts modulate growth factor signaling and extracellular matrix remodeling to regulate tumor metastasis. Biochem Soc Trans. (2017) 45:229–36. doi: 10.1042/BST20160387
80. Rice AJ, Cortes E, Lachowski D, Cheung BCH, Karim SA, Morton JP, et al. Matrix stiffness induces epithelial-mesenchymal transition and promotes chemoresistance in pancreatic cancer cells. Oncogenesis. (2017) 6:e352. doi: 10.1038/oncsis.2017.54
81. Peña-Romero AC and Orenes-Piñero E. Dual effect of immune cells within tumour microenvironment: pro- and anti-tumour effects and their triggers. Cancers (Basel). (2022) 14:1681. doi: 10.3390/cancers14071681
82. Maibach F, Sadozai H, Seyed Jafari SM, Hunger RE, and Schenk M. Tumor-infiltrating lymphocytes and their prognostic value in cutaneous melanoma. Front Immunol. (2020) 11:2105. doi: 10.3389/fimmu.2020.02105
83. Chen DS and Mellman I. Oncology meets immunology: the cancer-immunity cycle. Immunity. (2013) 39:1–10. doi: 10.1016/j.immuni.2013.07.012
84. Guo Q, Huang F, Goncalves C, Del Rincón SV, and Miller WH Jr. Translation of cancer immunotherapy from the bench to the bedside. Adv Cancer Res. (2019) 143:1–62. doi: 10.1016/bs.acr.2019.03.001
85. Woan KV and Miller JS. Harnessing natural killer cell antitumor immunity: from the bench to bedside. Cancer Immunol Res. (2019) 7:1742–7. doi: 10.1158/2326-6066.CIR-19-0404
86. Anderson NR, Minutolo NG, Gill S, and Klichinsky M. Macrophage-based approaches for cancer immunotherapy. Cancer Res. (2021) 81:1201–8. doi: 10.1158/0008-5472.CAN-20-2990
87. Wu H, Li P, Shao N, Ma J, Ji M, Sun X, et al. Aberrant expression of Treg-associated cytokine IL-35 along with IL-10 and TGF-β in acute myeloid leukemia. Oncol Lett. (2012) 3:1119–23. doi: 10.3892/ol.2012.614
88. Sahai E, Astsaturov I, Cukierman E, DeNardo DG, Egeblad M, Evans RM, et al. A framework for advancing our understanding of cancer-associated fibroblasts. Nat Rev Cancer. (2020) 20:174–86. doi: 10.1038/s41568-019-0238-1
89. Baghban R, Roshangar L, Jahanban-Esfahlan R, Seidi K, Ebrahimi-Kalan A, Jaymand M, et al. Tumor microenvironment complexity and therapeutic implications at a glance. Cell Commun Signal. (2020) 18:59. doi: 10.1186/s12964-020-0530-4
90. Qin S, Xu L, Yi M, Yu S, Wu K, and Luo S. Novel immune checkpoint targets: moving beyond PD-1 and CTLA-4. Mol Cancer. (2019) 18:155. doi: 10.1186/s12943-019-1091-2
91. Buchbinder EI and Desai A. CTLA-4 and PD-1 pathways: similarities, differences, and implications of their inhibition. Am J Clin Oncol. (2016) 39:98–106. doi: 10.1097/COC.0000000000000239
92. Woo SR, Turnis ME, Goldberg MV, Bankoti J, Selby M, Nirschl CJ, et al. Immune inhibitory molecules LAG-3 and PD-1 synergistically regulate T-cell function to promote tumoral immune escape. Cancer Res. (2012) 72:917–27. doi: 10.1158/0008-5472.CAN-11-1620
93. Harris AL. Hypoxia–a key regulatory factor in tumour growth. Nat Rev Cancer. (2002) 2:38–47. doi: 10.1038/nrc704
94. Chaturvedi P, Gilkes DM, Takano N, and Semenza GL. Hypoxia-inducible factor-dependent signaling between triple-negative breast cancer cells and mesenchymal stem cells promotes macrophage recruitment. Proc Natl Acad Sci USA. (2014) 111:E2120–9. doi: 10.1073/pnas.1406655111
95. Fridlender ZG and Albelda SM. Tumor-associated neutrophils: friend or foe? Carcinogenesis. (2012) 33:949–55. doi: 10.1093/carcin/bgs123
96. Kalluri R. The biology and function of fibroblasts in cancer. Nat Rev Cancer. (2016) 16:582–98. doi: 10.1038/nrc.2016.73
97. Beatty GL and Gladney WL. Immune escape mechanisms as a guide for cancer immunotherapy. Clin Cancer Res. (2015) 21:687–92. doi: 10.1158/1078-0432.CCR-14-1860
98. Polyak K, Haviv I, and Campbell IG. Co-evolution of tumor cells and their microenvironment. Trends Genet. (2009) 25:30–8. doi: 10.1016/j.tig.2008.10.012
99. Yang Y, Yang Y, Yang J, Zhao X, and Wei X. Tumor microenvironment in ovarian cancer: function and therapeutic strategy. Front Cell Dev Biol. (2020) 8:758. doi: 10.3389/fcell.2020.00758
100. Mori Y, Okimoto Y, Sakai H, Kanda Y, Ohata H, Shiokawa D, et al. Targeting PDGF signaling of cancer-associated fibroblasts blocks feedback activation of HIF-1α and tumor progression of clear cell ovarian cancer. Cell Rep Med. (2024) 5:101532. doi: 10.1016/j.xcrm.2024.101532
101. Atiya HI, Frisbie L, Goldfeld E, Orellana T, Donnellan N, Modugno F, et al. Endometriosis-associated mesenchymal stem cells support ovarian clear cell carcinoma through iron regulation. Cancer Res. (2022) 82:4680–93. doi: 10.1158/0008-5472.CAN-22-1294
102. Oda K, Hamanishi J, Matsuo K, and Hasegawa K. Genomics to immunotherapy of ovarian clear cell carcinoma: unique opportunities for management. Gynecol Oncol. (2018) 151:381–9. doi: 10.1016/j.ygyno.2018.09.001
103. Hamanishi J, Mandai M, Ikeda T, Minami M, Kawaguchi A, Murayama T, et al. Safety and antitumor activity of anti-PD-1 antibody, nivolumab, in patients with platinum-resistant ovarian cancer. J Clin Oncol. (2015) 33:4015–22. doi: 10.1200/JCO.2015.62.3397
104. Willis BC, Sloan EA, Atkins KA, Stoler MH, and Mills AM. Mismatch repair status and PD-L1 expression in clear cell carcinomas of the ovary and endometrium. Mod Pathol. (2017) 30:1622–32. doi: 10.1038/modpathol.2017.67
105. Cheng B, Liang H, Jiang T, Chen J, and Wang G. Characterization of PD-L1 expression and its prognostic value in patients with ovarian cancer. Transl Cancer Res. (2018) 7:1271–81. doi: 10.21037/tcr.2018.10.11
106. Devlin MJ, Miller R, Laforets F, Kotantaki P, Garsed DW, Kristeleit R, et al. The tumor microenvironment of clear-cell ovarian cancer. Cancer Immunol Res. (2022) 10:1326–39. doi: 10.1158/2326-6066.CIR-22-0407
107. Cassar E, Kartikasari AER, and Plebanski M. Regulatory T cells in ovarian carcinogenesis and future therapeutic opportunities. Cancers (Basel). (2022) 14:5488. doi: 10.3390/cancers14225488
108. Kim EH, Sullivan JA, Plisch EH, Tejera MM, Jatzek A, Choi KY, et al. Signal integration by Akt regulates CD8 T cell effector and memory differentiation. J Immunol. (2012) 188:4305–14. doi: 10.4049/jimmunol.1103568
109. Hemon P, Jean-Louis F, Ramgolam K, Brignone C, Viguier M, Bachelez H, et al. MHC class II engagement by its ligand LAG-3 (CD223) contributes to melanoma resistance to apoptosis. J Immunol. (2011) 186:5173–83. doi: 10.4049/jimmunol.1002050
110. Efimova OV and Kelley TW. Induction of granzyme B expression in T-cell receptor/CD28-stimulated human regulatory T cells is suppressed by inhibitors of the PI3K-mTOR pathway. BMC Immunol. (2009) 10:59. doi: 10.1186/1471-2172-10-59
111. Lastwika KJ, Wilson W 3rd, Li QK, Norris J, Xu H, Ghazarian SR, et al. Control of PD-L1 expression by oncogenic activation of the AKT-mTOR pathway in non-small cell lung cancer. Cancer Res. (2016) 76:227–38. doi: 10.1158/0008-5472.CAN-14-3362
112. Zaitsu S, Yano M, Adachi S, Miwa M, Katoh T, Kawano Y, et al. Lymphocyte-activation gene 3 protein expression in tumor-infiltrating lymphocytes is associated with a poor prognosis of ovarian clear cell carcinoma. J Ovarian Res. (2023) 16:93. doi: 10.1186/s13048-023-01179-1
113. Bitler BG, Wu S, Park PH, Hai Y, Aird KM, Wang Y, et al. ARID1A-mutated ovarian cancers depend on HDAC6 activity. Nat Cell Biol. (2017) 19:962–73. doi: 10.1038/ncb3582
114. Goode EL, Block MS, Kalli KR, Vierkant RA, Chen W, Fogarty ZC, et al. Dose-response association of CD8+ tumor-infiltrating lymphocytes and survival time in high-grade serous ovarian cancer. JAMA Oncol. (2017) 3:e173290. doi: 10.1001/jamaoncol.2017.3290
115. Kim SR, Cloutier BT, Leung S, Cochrane D, Britton H, Pina A, et al. Molecular subtypes of clear cell carcinoma of the endometrium: opportunities for prognostic and predictive stratification. Gynecol Oncol. (2020) 158:3–11. doi: 10.1016/j.ygyno.2020.04.043
116. Zhan J, Zhang M, Zhou L, and He C. Combination of immune checkpoint blockade and targeted gene regulation of angiogenesis for facilitating antitumor immunotherapy. Front Bioeng Biotechnol. (2023) 11:1065773. doi: 10.3389/fbioe.2023.1065773
117. Moore KN, Bookman M, Sehouli J, Miller A, Anderson C, Scambia G, et al. Atezolizumab, bevacizumab, and chemotherapy for newly diagnosed stage III or IV ovarian cancer: placebo-controlled randomized phase III trial (IMagyn050/GOG 3015/ENGOT-OV39). J Clin Oncol. (2021) 39:1842–55. doi: 10.1200/JCO.21.00306
118. Hamanishi J, Takeshima N, Katsumata N, Ushijima K, Kimura T, Takeuchi S, et al. Nivolumab versus gemcitabine or pegylated liposomal doxorubicin for patients with platinum-resistant ovarian cancer: open-label, randomized trial in Japan (NINJA). J Clin Oncol. (2021) 39:3671–81. doi: 10.1200/JCO.21.00334
119. Matulonis UA, Shapira-Frommer R, Santin AD, Lisyanskaya AS, Pignata S, Vergote I, et al. Antitumor activity and safety of pembrolizumab in patients with advanced recurrent ovarian cancer: results from the phase II KEYNOTE-100 study. Ann Oncol. (2019) 30:1080–7. doi: 10.1093/annonc/mdz135
120. Zamarin D, Burger RA, Sill MW, Powell DJ Jr, Lankes HA, Feldman MD, et al. Randomized phase II trial of nivolumab versus nivolumab and ipilimumab for recurrent or persistent ovarian cancer: an NRG Oncology study. J Clin Oncol. (2020) 38:1814–23. doi: 10.1200/JCO.19.02059
121. Dizon DS, Mathews CA, David SM, Machan JT, Hadfield MJ, Marks EI, et al. Final results of BrUOG 354: a randomized phase II trial of nivolumab alone or in combination with ipilimumab for people with ovarian and other extra-renal clear cell carcinomas. J Clin Oncol. (2024) 42:LBA5500. doi: 10.1200/JCO.2024.42.17_suppl.LBA5500
122. Makker V, Colombo N, Casado Herráez A, Santin AD, Colomba E, Miller DS, et al. Lenvatinib plus pembrolizumab for advanced endometrial cancer. N Engl J Med. (2022) 386:437–48. doi: 10.1056/NEJMoa2108330
123. Marth C, Tarnawski R, Tyulyandina A, Pignata S, Gilbert L, Kaen D, et al. Phase 3, randomized, open-label study of pembrolizumab plus lenvatinib versus chemotherapy for first-line treatment of advanced or recurrent endometrial cancer: ENGOT-en9/LEAP-001. Int J Gynecol Cancer. (2022) 32:93–100. doi: 10.1136/ijgc-2021-003017
124. Kim BG, Choi CH, Ngoi N, Tan D, Kim JW, and Kim JW. Preliminary efficacy of pembrolizumab plus lenvatinib in recurrent clear cell gynecological cancer: phase II LARA trial (GCGS-OV4/APGOT-OV3). Presented at: 39th Annu Meeting Korean Soc Gynecologic Oncol. (2024). doi: 10.3802/jgo.2024.35.S2.P21
125. Pembrolizumab and lenvatinib in clear cell ovarian cancer . Available online at: https://clinicaltrials.gov/study/NCT05296512.
126. González-Martín A, Chung HC, Saada-Bouzid E, Yanez E, Senellart H, Cassier PA, et al. Lenvatinib plus pembrolizumab for patients with previously treated advanced ovarian cancer: results from the phase 2 multicohort LEAP-005 study. Gynecol Oncol. (2024) 186:182–90. doi: 10.1016/j.ygyno.2024.04.011
127. McNamara B, Bellone S, Demirkiran C, Hartwich TMP, and Santin AD. Pembrolizumab and lenvatinib in recurrent ovarian clear cell carcinoma resistant to chemotherapy. Gynecol Oncol Rep. (2023) 48:101218. doi: 10.1016/j.gore.2023.101218
128. A study of pembrolizumab in patients with advanced gynaecological clear cell cancer (PEACOCC) . Available online at: https://clinicaltrials.gov/study/NCT03425565.
129. Sintilimab plus bevacizumab in recurrent/persistent ovarian clear cell carcinoma (INOVA). Available online at: https://clinicaltrials.gov/study/NCT04735861.
130. Liu X, Xia B, Zhang W, Sun L, Feng C, Huang Y, et al. 522MO Preliminary results of sintilimab (Sin)+bevacizumab (Bev) in recurrent/persistent ovarian clear cell carcinoma (INOVA): a multicenter, single-arm, phase II trial. Ann Oncol. (2022) 33:S235–82. doi: 10.1016/annonc/annonc1054
131. Study on pembrolizumab in recurrent, platinum resistant, CPS >1 positive ovarian, fallopian tube and primary peritoneal cancer patients (MITO 27) . Available online at: https://www.clinicaltrials.gov/study/NCT04375956.
132. Tan DSP, Choi CH, Ngoi N, Sun H, Heong V, Ow SGW, et al. A multicenter phase II randomized trial of durvalumab (D) versus physician’s choice chemotherapy (PCC) in patients with recurrent ovarian clear cell adenocarcinoma (MOCCA/APGOT-OV2/GCGS-OV3). J Clin Oncol. (2022) 40:5565. doi: 10.1200/JCO.2022.40.16_suppl.5565
133. A study evaluating the efficacy and safety of biomarker-driven therapies in patients with persistent or recurrent rare epithelial ovarian tumors (BOUQUET) . Available online at: https://clinicaltrials.gov/study/NCT04931342.
134. Ray-Coquard IL, Pignata S, Lee JY, Coleman RL, Brown J, Kim JW, et al. 747MO First results from the ENGOT-GYN2/GOG-3051/BOUQUET phase II biomarker-directed platform study: cobimetinib or atezolizumab + bevacizumab for persistent/recurrent rare epithelial ovarian cancer. Ann Oncol. (2023) 34:S511–2. doi: 10.1016/j.annonc.2023.09.1926
135. BrUOG 354 nivolumab +/- ipilimumab for ovarian and extra-renal clear cell carcinomas . Available online at: https://clinicaltrials.gov/study/NCT03355976.
136. Trial of lenvatinib plus pembrolizumab in recurrent gynecological clear cell adenocarcinomas (LARA) . Available online at: https://clinicaltrials.gov/study/NCT04699071.
137. EON: A single-arm phase II study of etigilimab (OMP-313M32) in combination with checkpoint inhibition (Nivolumab) in patients with platinum-resistant, recurrent epithelial ovarian cancer . Available online at: https://clinicaltrials.gov/study/NCT05026606.
138. A study of xmAb20717 (Vudalimab)in patients with selected advanced gynecologic and genitourinary Malignancies . Available online at: https://clinicaltrials.gov/study/NCT05032040.
139. Fukumoto T, Fatkhutdinov N, Zundell JA, Tcyganov EN, Nacarelli T, Karakashev S, et al. HDAC6 inhibition synergizes with anti-PD-L1 therapy in ARID1A-inactivated ovarian cancer. Cancer Res. (2019) 79:5482–9. doi: 10.1158/0008-5472.CAN-19-1302
140. Jeong W, Park SR, Rapisarda A, Fer N, Kinders RJ, Chen A, et al. Weekly EZN-2208 (PEGylated SN-38) in combination with bevacizumab in patients with refractory solid tumors. Invest New Drugs. (2014) 32:340–6. doi: 10.1007/s10637-013-0048-3
141. Norris RE, Shusterman S, Gore L, Muscal JA, Macy ME, Fox E, et al. Phase 1 evaluation of EZN-2208, a polyethylene glycol conjugate of SN38, in children, adolescents and young adults with relapsed or refractory solid tumors. Pediatr Blood Cancer. (2014) 61:1792–7. doi: 10.1002/pbc.25105
142. Luo F, Lu FT, Cao JX, Ma WJ, Xia ZF, Zhan JH, et al. HIF-1α inhibition promotes the efficacy of immune checkpoint blockade in the treatment of non-small cell lung cancer. Cancer Lett. (2022) 531:39–56. doi: 10.1016/j.canlet.2022.01.027
143. Lin YC, Wen KC, Sung PL, Chou YT, Liew PL, Chen LY, et al. Complete remission of heavily treated ovarian clear cell carcinoma with ARID1A mutations after pembrolizumab and bevacizumab combination therapy: a case report. J Ovarian Res. (2020) 13:143. doi: 10.1186/s13048-020-00751-3
144. Bent EH, Millan-Barea LR, Zhuang I, Goulet DR, Frose J, and Hemann MT. Microenvironmental IL-6 inhibits anti-cancer immune responses generated by cytotoxic chemotherapy. Nat Commun. (2021) 12:6218. doi: 10.1038/s41467-021-26407-4
145. Silva JR, Sales NS, Silva MO, Aps LRMM, Moreno ACR, Rodrigues EG, et al. Expression of a soluble IL-10 receptor enhances the therapeutic effects of a papillomavirus-associated antitumor vaccine in a murine model. Cancer Immunol Immunother. (2019) 68:753–63. doi: 10.1007/s00262-018-02297-2
146. Ni G, Wang Y, Cummins S, Walton S, Mounsey K, Liu X, et al. Inhibitory mechanism of peptides with a repeating hydrophobic and hydrophilic residue pattern on interleukin-10. Hum Vaccin Immunother. (2017) 13:518–27. doi: 10.1080/21645515.2016.1238537
147. Berezhnoy A, Stewart CA, McNamara JO 2nd, Thiel W, Giangrande P, Trinchieri G, et al. Isolation and optimization of murine IL-10 receptor blocking oligonucleotide aptamers using high-throughput sequencing. Mol Ther. (2012) 20:1242–50. doi: 10.1038/mt.2012.18
148. Alpelisib . FDA. Available online at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/212526s000lbl.pdf.
149. Passarelli A, Carbone V, Pignata S, Mazzeo R, Lorusso D, Scambia G, et al. Alpelisib for PIK3CA-mutated advanced gynecological cancers: First clues of clinical activity. Gynecol Oncol. (2024) 183:61–7. doi: 10.1016/j.ygyno.2024.02.029
150. Passarelli A, Ventriglia J, Pisano C, Cecere SC, Napoli MD, Rossetti S, et al. The way to precision medicine in gynecologic cancers: The first case report of an exceptional response to alpelisib in a PIK3CA-mutated endometrial cancer. Front Oncol. (2023) 12:1088962. doi: 10.3389/fonc.2022.1088962
Keywords: ovarian clear cell carcinoma, ARID1A mutations, tumor microenvironment, immune checkpoint inhibitors, combination immunotherapy
Citation: Passarelli A, Cecere SC, Ventriglia J, Pisano C, De Cecio R, Rossetti S, Tambaro R, Di Napoli M, Lobianco L, Calvanese G, Lamia MR, Perri E, Peluso MS, Scarpa E, Stilo S, Fiore F, Setola SV, Califano D and Pignata S (2025) The immunotherapy era in ovarian clear cell carcinoma: current evidence and future perspective. Front. Immunol. 16:1661048. doi: 10.3389/fimmu.2025.1661048
Received: 07 July 2025; Accepted: 11 November 2025; Revised: 23 October 2025;
Published: 26 November 2025.
Edited by:
Nicole James, Women & Infants Hospital of Rhode Island, United StatesReviewed by:
Sajad A Dar, Jazan University, Saudi ArabiaAnna Pawłowska-Łachut, Medical University of Lublin, Poland
Copyright © 2025 Passarelli, Cecere, Ventriglia, Pisano, De Cecio, Rossetti, Tambaro, Di Napoli, Lobianco, Calvanese, Lamia, Perri, Peluso, Scarpa, Stilo, Fiore, Setola, Califano and Pignata. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Anna Passarelli, YW5uYS5wYXNzYXJlbGxpQGlzdGl0dXRvdHVtb3JpLm5hLml0