Song Yue
Tao Wen2†
Xiaozhu Liu
Yue Liu
Shengxian Peng- 1Department of Clinical Laboratory, The First Affiliated Hospital of Chengdu Medical College, Chengdu, China
- 2Department of Clinical Blood Transfusion, Sichuan Provincial People’s Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
- 3Department of Critical Care Medicine, Clinical and Research Center on Acute Lung Injury, Emergency and Critical Care Center, Beijing Shijitan Hospital, Capital Medical University, Beijing, China
- 4Scientific Research Department, First People’s Hospital of Zigong City, Zigong, China
- 5Department of Pediatrics, First People’s Hospital of Zigong City, Zigong, China
Ovarian cancer remains one of the most lethal gynecologic malignancies, with high recurrence rates and poor prognosis, particularly in platinum-resistant cases. Immune checkpoint inhibitors (ICIs), especially those targeting PD-1/PD-L1, have demonstrated success in multiple malignancies, yet their efficacy in ovarian cancer has been limited. Monotherapy with ICIs yields low response rates, prompting extensive investigations into combination strategies with chemotherapy, PARP inhibitors, and antiangiogenic agents. Some dual or triple regimens have shown promising activity, especially in biomarker-selected populations. However, immune resistance, immunosuppressive tumor microenvironment (TME), and biomarker heterogeneity remain significant barriers. This review summarizes the latest clinical progress in ICI-based therapies for ovarian cancer, evaluates current predictive biomarkers such as PD-L1 expression, TMB, and homologous recombination deficiency (HRD), and highlights the safety and toxicity profiles of immunotherapy. We also discuss the limitations of current clinical trials and the unmet need for precise immunotherapeutic strategies. Understanding the molecular and immunologic landscape of ovarian cancer is critical for identifying patients most likely to benefit from ICIs and guiding future clinical development.
1 Introduction
Ovarian cancer is one of the most common and lethal gynecological malignancies (1, 2). Standard-of-care treatment consists of cytoreductive surgery followed by platinum-based chemotherapy (3). Although the incorporation of targeted therapies has modestly improved outcomes, long-term prognosis remains dismal, especially for patients with platinum-resistant or recurrent disease (4). In recent years, immunotherapy—particularly immune checkpoint inhibitors (ICIs)—has emerged as a promising therapeutic option (5–7). In several malignancies, including non-small cell lung cancer, ICIs targeting programmed death 1 (PD-1) or its ligand PD-L1 have demonstrated substantial clinical benefit (8–11).
In ovarian cancer, however, their efficacy remains modest. Clinical trials have shown that PD-1/PD-L1 inhibitors used as second-line or later treatments in recurrent ovarian cancer yielded limited improvements in overall survival (OS) (12). A principal barrier to effective immunotherapy lies in the immunosuppressive nature of the ovarian tumor microenvironment (TME) (13–16). Notably, regulatory T cells (Tregs) are frequently enriched in the ovarian TME, where they attenuate cytotoxic T cell responses and facilitate immune evasion (17). This review outlines recent advances, persistent challenges, and future directions in ovarian cancer immunotherapy, aiming to inform the development of more effective, context-specific approaches.
2 Mechanisms of immune exclusion and resistance to immune checkpoint inhibitors in ovarian cancer
Ovarian cancer is characterized by poor infiltration of effector T lymphocytes and immune exclusion (17). This immunologically “cold” phenotype arises from a confluence of tumor-intrinsic and microenvironmental factors. Notably, ovarian cancer cells often downregulate major histocompatibility complex class I (MHC-I) molecules, thereby evading recognition and elimination by cytotoxic T lymphocytes (18, 19). Concurrently, the tumor microenvironment impairs dendritic cell (DC) maturation and antigen-presenting function, resulting in suboptimal T cell priming and weakened adaptive immune activation (20, 21). Tumor cells and associated stromal components actively recruit immunosuppressive populations, including MDSCs and Tregs, which inhibit cytotoxic immune responses via direct cell–cell contact and cytokine-mediated suppression (22). Notably, IL-10 and TGF-β, abundantly secreted by tumor and immune cells in the TME, dampen effector T cell proliferation and skew macrophage polarization toward the immunosuppressive M2 phenotype (23, 24). Moreover, tumor-derived metabolites such as lactate and adenosine further exacerbate immune dysfunction. Many ovarian cancers harbor defects in cGAS–STING pathway, a central axis in type I interferon (IFN) induction, leading to impaired type I IFN production, defective DC recruitment and maturation, and insufficient activation of adaptive immunity (25, 26). In the absence of STING signaling, DCs fail to mature effectively, compromising antigen presentation and CD8+ T cell priming. This cascade ultimately results in reduced CTL infiltration and reinforces tumor immune evasion (27, 28).
Immune checkpoints are regulatory molecules expressed on immune cells that modulate immune activation. Among them, PD-1, PD-L1, and cytotoxic T-lymphocyte antigen 4 (CTLA-4) have been most extensively characterized (29–31). Dysregulated expression of these molecules contributes to tumor progression and immune evasion (32). Immune checkpoint inhibitors restore antitumor immunity by interrupting these inhibitory pathways (33). Specifically, PD-1/PD-L1 inhibitors block the interaction between PD-1 on T cells and PD-L1 on tumor cells, thereby reinvigorating T cell–mediated cytotoxicity. In ovarian cancer, PD-1/PD-L1 blockade has been primarily explored in the recurrent setting (34–36). However, the efficacy of ICI monotherapy has been limited, with overall response rates (ORRs) typically approximating 10% (34). In the phase II KEYNOTE-100 trial, which enrolled 376 patients with recurrent ovarian cancer, pembrolizumab monotherapy yielded a median OS of 19 months. Higher response rates were observed in patients with elevated PD-L1 combined positive scores (CPS), although no definitive correlation between CPS and clinical outcome was confirmed (37). Notably, a phase III randomized trial involving platinum-resistant ovarian cancer patients demonstrated that nivolumab monotherapy significantly prolonged progression-free survival (PFS) compared to chemotherapy, highlighting its potential benefit in this therapeutically challenging population (38).
3 Combination of ICIs and anti-tumor drugs
3.1 Combination of ICIs with other ICIs
Monotherapy with ICIs has yielded modest efficacy in ovarian cancer, prompting investigation into “dual ICI therapy” (39, 40). The NRG GY003 trial (41) evaluated nivolumab plus ipilimumab in 100 patients with recurrent ovarian cancer following one to three prior lines of platinum-based chemotherapy. Compared to nivolumab monotherapy, the combination of nivolumab and ipilimumab significantly improved ORR (42). CTLA-4 and PD-1 modulate distinct phases of T cell activity. CTLA-4 blockade enhances priming and expansion of naïve T cells, while PD-1 inhibition reactivates exhausted effector T cells within the tumor microenvironment (43–45). This complementary interplay forms the rationale for combined blockade. However, in ovarian cancer, this synergy is muted, likely due to its immunologically “cold” microenvironment—characterized by sparse T cell infiltration, limited dendritic cell maturation, and low neoantigen burden (46). These features impair antigen presentation and effector T cell activation, thereby attenuating the therapeutic impact of dual checkpoint blockade. Similarly, neither concurrent nor sequential administration of anti-CTLA-4 and anti-PD-1 antibodies demonstrated significant progression-free survival (PFS) benefits over PD-1 monotherapy (47). In the monotherapy cohort, 32% of patients achieved stable disease (SD), while the dual-ICI arm yielded partial responses (PR) in 9% of patients. Expanding on this approach, the phase II KOGC3045 trial assessed nivolumab combined with chemotherapy in platinum-resistant or refractory ovarian cancer (48). The combination yielded an ORR of 32%, with SD in 10% and a disease control rate of 35%. Subgroup analysis revealed superior PFS in the combination arm versus paclitaxel monotherapy (Table 1).
Table 1. Immune checkpoint inhibitor monotherapy and combination strategies in ovarian cancer.
3.2 Combination of ICIs with chemotherapy
Chemotherapeutic agents have been demonstrated to attenuate tumor-induced immunosuppression by suppressing Tregs and myeloid-derived suppressor cells (MDSCs), while simultaneously enhancing tumor immunogenicity through the induction of immunogenic cell death (49, 50). In a phase II multicenter trial involving 26 patients with platinum-resistant ovarian cancer, the combination of pembrolizumab and pegylated liposomal doxorubicin yielded an ORR of 26%. Similarly, nivolumab combined with pegylated liposomal doxorubicin achieved an ORR of 23% in a cohort of 40 patients with recurrent disease (51). In the larger phase III JAVELIN Ovarian 200 trial, 566 patients with platinum-resistant or refractory ovarian cancer were randomized to receive either pegylated liposomal doxorubicin alone or in combination with the anti–PD-L1 antibody avelumab (52). The combination arm demonstrated a higher ORR and a modest improvement in PFS, although OS did not differ significantly.
3.3 ICIs combined with PARP inhibitors
Poly (ADP-ribose) polymerase (PARP) inhibitors not only disrupt DNA repair in tumor cells but also upregulate PD-L1 expression, thereby enhancing tumor immunogenicity. The strategy of co-administering PARP inhibitors and ICIs is under active clinical investigation in ovarian cancer. In the MEDIOLA trial, olaparib plus durvalumab demonstrated a 72% objective response rate (ORR) in relapsed, platinum-sensitive ovarian cancer patients naïve to PARP inhibitors, with a heightened ORR of 81% among BRCA1/2-mutated individuals (53). Similarly, the TOPACIO study reported an ORR of ~18% for the niraparib–pembrolizumab combination in 62 patients with recurrent ovarian cancer (54). By contrast, the GOG-3032 trial—assessing PARP inhibition alongside PD-1 blockade in platinum-resistant disease—achieved a modest ORR of 7% and was subsequently terminated due to limited efficacy (55). BRCA mutations and homologous recombination deficiency (HRD) compromise homologous recombination repair (HRR), resulting in the accumulation of cytosolic DNA fragments. These fragments activate the cGAS–STING pathway, triggering type I interferon and pro-inflammatory cytokine release, which in turn enhances dendritic cell maturation, antigen presentation, and CD8+ T cell infiltration. Additionally, HRD-induced genomic instability elevates neoantigen burden, potentially augmenting responsiveness to immune checkpoint blockade.
3.4 Combination of ICIs and anti-angiogenic agents
Anti-angiogenic agents can reprogram the tumor vasculature and microenvironment to augment antitumor immunity and potentiate the response to immune checkpoint blockade (56). Pathological angiogenesis in tumors not only disrupts vessel integrity but also hinders immune cell infiltration and sustains an immunosuppressive milieu. In contrast, vascular normalization facilitates immune cell trafficking and enhances effector function (57). Several clinical efforts have evaluated the therapeutic synergy of combining PD-1/PD-L1 blockade with anti-angiogenic agents in recurrent ovarian cancer (58, 59). However, the clinical efficacy of such combinations remains limited, with ORRs typically below 20%, and the success of dual blockade strategies is often molecule-dependent. For instance, the LEAP-005 trial, which evaluated lenvatinib plus pembrolizumab in heavily pretreated patients with recurrent ovarian cancer, reported an ORR of merely 10% among 31 participants who had received at least two prior lines of therapy (60). In contrast, a singe study assessing the PD-L1 inhibitor TQB2450 in combination with the multi-targeted anti-angiogenic agent anlotinib in platinum-resistant or refractory ovarian cancer achieved an ORR of 47% in 34 evaluable patients (61).
3.5 Combination of ICIs with anti-angiogenic agents and PARP inhibitors
Preclinical evidence indicates that anti-angiogenic therapy may reduce tumor perfusion and oxygenation, inducing hypoxia that suppresses homologous recombination (HR) repair genes such as BRCA1/2 (62). This hypoxic milieu functionally mimics BRCA mutations even in wild-type tumors, thereby fostering a state of HR deficiency. Notably, VEGF inhibition downregulates key HR mediators including RAD51 and BRCA1, impairing double-strand break repair and shifting reliance toward error-prone pathways. This synthetic vulnerability underpins the rationale for combining ICIs, anti-angiogenic agents, and PARP inhibitors in ovarian cancer. Nevertheless, clinical trials in BRCA–wild-type populations have shown limited benefit. For example, the OPAL trial by the IMagyn050 study group reported an ORR of only 20% with durvalumab, olaparib, and bevacizumab in platinum-sensitive recurrent ovarian cancer (63). A clinical trial in 40 patients with recurrent ovarian cancer showed that pembrolizumab combined with pegylated liposomal doxorubicin yielded an ORR of 48%, with a median PFS of 10 months (64). In the ATALANTE trial, newly diagnosed patients received six cycles of standard chemotherapy plus atezolizumab, followed by maintenance therapy; however, after a median follow-up of three years, no statistically significant PFS benefit was observed compared to placebo (65). Similarly, the IMagyn050 study, which included patients with stage III–IV ovarian cancer, demonstrated that the addition of atezolizumab to bevacizumab, carboplatin, and paclitaxel failed to improve PFS, even in the PD-L1–positive subgroup (66). By contrast, the DUO-O trial targeting BRCA1/2 wild-type advanced ovarian cancer revealed that a triplet maintenance regimen of durvalumab, olaparib, and bevacizumab, following standard chemotherapy plus durvalumab, conferred superior PFS over durvalumab and bevacizumab alone (67). Notably, recent data presented at ASCO 2024 involving a late-line cohort treated with ICIs showed no significant survival benefit.
4 Challenges in the clinical application of ICIs in ovarian cancer
4.1 Adverse events and management of ICIs
Immune checkpoint inhibitor therapy is associated with adverse events (AEs) in approximately 30% of patients, though the severity and frequency vary by regimen. Notably, severe AEs are observed in 0.4% of patients receiving PD-1 monotherapy and rise to 1.2% when PD-1 inhibitors are combined with CTLA-4 blockade (68). In clinical trials involving ICIs for ovarian cancer, the most commonly reported AEs include fatigue, nausea and vomiting, arthralgia, and hypothyroidism (69). Less frequent but more serious AEs include immune-related hepatitis, pneumonitis, and myocarditis. The management of ICI-related AEs in ovarian cancer generally follows protocols established in other solid tumors (70). In addition to monitoring for common toxicities such as rash, neurological symptoms, hematological abnormalities, and endocrine dysfunction, Grade 1 AEs generally warrant observation, whereas most Grade 2 toxicities, particularly cutaneous and endocrine, can be mitigated with corticosteroids and supportive care, permitting treatment continuation. In contrast, Grade 3 events necessitate temporary discontinuation and immunosuppressive therapy, while Grade 4 reactions often mandate permanent cessation. Notably, no definitive association has been established between AE incidence and therapeutic benefit in ovarian cancer.
4.2 Biomarkers predictive of ICIs efficacy
The human DNA mismatch repair (MMR) system safeguards genomic integrity by correcting replication-associated errors. Deficiency in this system (dMMR) leads to the accumulation of mutations and culminates in microsatellite instability-high (MSI-H) status, a molecular hallmark that enhances tumor immunogenicity via increased neoantigen generation and subsequent immune surveillance activation (71). Tumor mutational burden (TMB), defined as the total number of somatic mutations within tumor genomes, serves as a surrogate for neoantigen load. Tumors exhibiting high TMB (TMB-H) are thus theoretically more responsive to immune checkpoint blockade. Supporting this, pembrolizumab monotherapy has been approved under a tumor-agnostic indication for patients with recurrent ovarian cancer harboring dMMR/MSI-H or TMB-H, as demonstrated in the KEYNOTE-158 trial (66). Homologous recombination deficiency (HRD)—typically resulting from BRCA mutations or defects in DNA repair pathways—represents a validated biomarker for sensitivity to PARP inhibitors and platinum-based chemotherapy in ovarian cancer (72, 73). However, its predictive value for immunotherapy efficacy remains unresolved. Subgroup analyses from immune checkpoint inhibitor monotherapy trials in ovarian cancer reveal no consistent association between BRCA mutational status and clinical benefit (74, 75). Notably, tumors harboring BRCA mutations but lacking HRD signatures exhibit reduced responsiveness to both PARP inhibition and immunotherapy. PD-L1 expression, though widely employed as a predictive biomarker across malignancies, demonstrates inconsistent prognostic utility in ovarian cancer (Table 2).
Table 2. Mechanisms of immune resistance in ovarian cancer and corresponding translational strategies.
In the IMagyn050 trial (18), 24% of enrolled patients harbored BRCA1/2 mutations and 46% were homologous recombination deficiency (HRD)-positive. However, the addition of atezolizumab to standard therapy failed to confer a significant progression-free survival (PFS) advantage in the HRD-positive subgroup. Although PD-L1 expression has been suggested as a predictive biomarker, its utility in ovarian cancer remains controversial (44, 45). For instance, one study found that PD-L1 positivity in tumor-infiltrating immune cells was not associated with improved prognosis, nor did PD-L1 status correlate with clinical outcomes in epithelial ovarian cancer (46). Nevertheless, PD-L1 may retain some prognostic significance. In the KEYNOTE-100 trial (66), a positive correlation was observed between PD-L1 expression levels and response to pembrolizumab. Similarly, in IMagyn050 (47), although no significant PFS improvement was detected in patients with PD-L1 immune cell expression ≥1%, exploratory analyses revealed that individuals with expression ≥5% derived greater benefit from combined immunotherapy. Furthermore, when PD-L1 expression was assessed using tumor cell scoring, patients with elevated PD-L1 in tumor cells experienced statistically significant benefit from immunotherapy (76). These findings underscore that the prognostic and predictive value of PD-L1 in ovarian cancer is complex, varying with both the scoring methodology and threshold used. Overall, the identification of robust and reproducible biomarkers for immunotherapy responsiveness in ovarian cancer remains a critical unmet need and warrants continued investigation.
4.3 Limitations of immune checkpoint inhibitor application in ovarian cancer
The variable efficacy of ICIs in ovarian cancer may be attributed to intrinsic resistance mechanisms. Even in patients initially responsive to ICIs, tumor tissues may eventually acquire resistance during treatment. The recognized resistance-related factors include defective T cell infiltration and immune exclusion, as well as low MSI-H or TMB levels (77). According to biomarker subgroup analysis from the IMagyn050 trial (78), only 3% of ovarian cancer patients exhibited TMB ≥10 mutations/Mb, and merely 0.3% were MSI-H positive, indicating generally low PD-L1 expression levels in ovarian cancer tissues. Increasing tumor burden has been recognized as a negative prognostic factor in ICI therapy. Studies have shown that across multiple tumor types (including ovarian cancer), patients with higher tumor burden, liver metastases, or advanced-stage disease respond less favorably to immunotherapy. In the IMagyn050 trial, subgroup analysis revealed that patients with stage III ovarian cancer benefited from the addition of atezolizumab, whereas no benefit was observed in stage IV patients (79). Most immunotherapy trials in ovarian cancer have been conducted in recurrent or platinum-resistant disease populations, with high tumor burden, advanced stage, and poor prognosis (80). Very few studies focus on patients with R0 resection or early-stage disease, potentially underestimating the clinical benefit of ICIs (81). Additionally, ICIs may show higher efficacy in tumors of endometrial origin, such as ovarian endometrioid carcinoma and clear cell carcinoma, which are characterized by higher rates of mismatch repair deficiency and microsatellite instability, and thus more likely to respond to immunotherapy (82).
5 Conclusion
ICIs represent a promising yet still developing therapeutic avenue in the management of ovarian cancer. While monotherapy has yielded limited efficacy, especially in heavily pretreated or platinum-resistant patients, combination strategies have shown greater potential. Dual checkpoint blockade, ICIs combined with chemotherapy, PARP inhibitors, or antiangiogenic agents, and even triple therapies are under active exploration. Certain biomarker-defined subsets—such as patients with MSI-H/dMMR, high TMB, or BRCA mutations—may derive more benefit from immunotherapy, though these populations remain rare. The tumor immune microenvironment in ovarian cancer is often “cold,” with low T-cell infiltration and high immunosuppressive cell activity, which further limits response. Additionally, PD-L1 expression, though widely studied, offers inconsistent predictive value depending on detection methods and scoring systems.
Moving forward, several challenges must be addressed to fully integrate ICIs into standard ovarian cancer treatment. First, robust and reproducible biomarkers are urgently needed to identify responsive patients and guide therapeutic decisions. Second, the design of clinical trials must evolve to include patients with lower tumor burden or earlier-stage disease, who may benefit more from immunotherapy. Furthermore, a deeper understanding of the immune landscape, including mechanisms of resistance such as cGAS-STING defects and immune exhaustion, is crucial. Integrating omics-based profiling, spatial immunology, and single-cell technologies may help delineate new therapeutic targets. To accelerate clinical translation, future trials should prioritize HRD-positive and MSI-H ovarian cancer subtypes that are more likely to respond to ICIs, explore synergistic regimens combining ICIs with epigenetic modifiers, and leverage spatial transcriptomic profiling to uncover immune niches and enable precision immunotherapy. Ultimately, the success of ICIs in ovarian cancer will depend on precise patient stratification, rational combination regimens, and overcoming tumor-intrinsic immune resistance mechanisms.
Author contributions
SY: Writing – original draft. TW: Writing – original draft. XL: Writing – original draft. JT: Writing – original draft. YL: Writing – original draft. SP: Writing – original draft, Writing – review & editing.
Funding
The author(s) declared that financial support was not received for this work and/or its publication.
Conflict of interest
The author(s) declared that this work was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Generative AI statement
The author(s) declared that generative AI was not used in the creation of this manuscript.
Any alternative text (alt text) provided alongside figures in this article has been generated by Frontiers with the support of artificial intelligence and reasonable efforts have been made to ensure accuracy, including review by the authors wherever possible. If you identify any issues, please contact us.
Publisher’s note
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.
References
1. Force LM, Kocarnik JM, May ML, Bhangdia K, Crist A, Penberthy L, et al. The global, regional, and national burden of cancer, 1990-2023, with forecasts to 2050: a systematic analysis for the Global Burden of Disease Study 2023. Lancet. (2025) 406:1565–86. doi: 10.1016/S0140-6736(25)01635-6
2. Zhang P, Pei S, Wu L, Xia Z, Wang Q, Huang X, et al. Integrating multiple machine learning methods to construct glutamine metabolism-related signatures in lung adenocarcinoma. Front Endocrinol (Lausanne). (2023) 14:1196372. doi: 10.3389/fendo.2023.1196372
3. Li H, Sheng JJ, Zheng SA, Liu PW, Wu N, Zeng WJ, et al. Platinum-resistant ovarian cancer: From mechanisms to treatment strategies. Genes Dis. (2026) 13:101801. doi: 10.1016/j.gendis.2025.101801
4. Wang G, Yang H, Wang Y, and Qin J. Ovarian cancer targeted therapy: current landscape and future challenges. Front Oncol. (2025) 15:1535235. doi: 10.3389/fonc.2025.1535235
5. Tang Q, Chen Y, Li X, Long S, Shi Y, Yu Y, et al. The role of PD-1/PD-L1 and application of immune-checkpoint inhibitors in human cancers. Front Immunol. (2022) 13:964442. doi: 10.3389/fimmu.2022.964442
6. Xia Z, Chen S, He M, Li B, Deng Y, Yi L, et al. Editorial: Targeting metabolism to activate T cells and enhance the efficacy of checkpoint blockade immunotherapy in solid tumors. Front Immunol. (2023) 14:1247178. doi: 10.3389/fimmu.2023.1247178
7. Liu J, Su Y, Zhang C, Dong H, Yu R, Yang X, et al. NCOA3 impairs the efficacy of anti-PD-L1 therapy via HSP90α/EZH2/CXCL9 axis in colon cancer. Int Immunopharmacol. (2025) 155:114579. doi: 10.1016/j.intimp.2025.114579
8. Xia Y, Zhu H, Huang S, Guan X, Chen X, Zhang Q, et al. Remarkable response to pembrolizumab in PD-L1 overexpressing (≥ 50%) NSCLC and extracranial abscopal effect induced by brain radiotherapy: a case report. Front Oncol. (2025) 15:1652515. doi: 10.3389/fonc.2025.1652515
9. Newsome RC, Liu H, Agbodzi B, Gharaibeh RZ, Zhou L, and Jobin C. Microbial-derived immunostimulatory small molecule augments anti-PD-1 therapy in lung cancer. Cell Rep Med. (2026) 7:102519. doi: 10.1016/j.xcrm.2025.102519
10. Deng Y, Shi M, Yi L, Naveed Khan M, Xia Z, and Li X. Eliminating a barrier: Aiming at VISTA, reversing MDSC-mediated T cell suppression in the tumor microenvironment. Heliyon. (2024) 10:e37060. doi: 10.1016/j.heliyon.2024.e37060
11. Ke H, Li P, Li Z, Zeng X, Zhang C, Luo S, et al. Immune profiling of the macroenvironment in colorectal cancer unveils systemic dysfunction and plasticity of immune cells. Clin Transl Med. (2025) 15:e70175. doi: 10.1002/ctm2.70175
12. Zeng S, Liu D, Yu Y, Zou L, Jin X, Liu B, et al. Efficacy and safety of PD-1/PD-L1 inhibitors in the treatment of recurrent and refractory ovarian cancer: A systematic review and a meta-analysis. Front Pharmacol. (2023) 14:1111061. doi: 10.3389/fphar.2023.1111061
13. Jin W, Yang Q, Chi H, Wei K, Zhang P, Zhao G, et al. Ensemble deep learning enhanced with self-attention for predicting immunotherapeutic responses to cancers. Front Immunol. (2022) 13:1025330. doi: 10.3389/fimmu.2022.1025330
14. Xie H, Xi X, Lei T, Liu H, and Xia Z. CD8(+) T cell exhaustion in the tumor microenvironment of breast cancer. Front Immunol. (2024) 15:1507283. doi: 10.3389/fimmu.2024.1507283
15. Xiong J, Chi H, Yang G, Zhao S, Zhang J, Tran LJ, et al. Revolutionizing anti-tumor therapy: unleashing the potential of B cell-derived exosomes. Front Immunol. (2023) 14:1188760. doi: 10.3389/fimmu.2023.1188760
16. Chiang CL, Ma Y, Hou YC, Pan J, Chen SY, Chien MH, et al. Dual targeted extracellular vesicles regulate oncogenic genes in advanced pancreatic cancer. Nat Commun. (2023) 14:6692. doi: 10.1038/s41467-023-42402-3
17. Yan Y, Lu J, Luo H, Wang Z, Xu K, Wang L, et al. Decoding immune low-response states in ovarian cancer: insights from single-cell and spatial transcriptomics for precision immunotherapy. Front Immunol. (2025) 16:1667464. doi: 10.3389/fimmu.2025.1667464
18. Liu C, Yin Q, Wu Z, Li W, Huang J, Chen B, et al. Inflammation and immune escape in ovarian cancer: pathways and therapeutic opportunities. J Inflammation Res. (2025) 18:895–909. doi: 10.2147/JIR.S503479
19. Cornel AM, Mimpen IL, and Nierkens S. MHC class I downregulation in cancer: underlying mechanisms and potential targets for cancer immunotherapy. Cancers (Basel). (2020) 12:1760. doi: 10.3390/cancers12071760
20. Xiao Z, Wang R, Wang X, Yang H, Dong J, He X, et al. Impaired function of dendritic cells within the tumor microenvironment. Front Immunol. (2023) 14:1213629. doi: 10.3389/fimmu.2023.1213629
21. Lee JH, Choi SY, Jung NC, Song JY, Seo HG, Lee HS, et al. The effect of the tumor microenvironment and tumor-derived metabolites on dendritic cell function. J Cancer. (2020) 11:769–75. doi: 10.7150/jca.38785
22. Basurto-Olvera P, Serrano H, and Maldonado-Bernal C. Regulatory T cells in cancer: from immunosuppression to therapeutic targeting. Front Immunol. (2025) 16:1703211. doi: 10.3389/fimmu.2025.1703211
23. Xu C, Chen J, Tan M, and Tan Q. The role of macrophage polarization in ovarian cancer: from molecular mechanism to therapeutic potentials. Front Immunol. (2025) 16:1543096. doi: 10.3389/fimmu.2025.1543096
24. Cheng KC, Lin YH, Wu DS, Shih IM, and Wang TL. Macrophages and neutrophils in ovarian cancer microenvironment. Front Immunol. (2025) 16:1677441. doi: 10.3389/fimmu.2025.1677441
25. de Queiroz N, Xia T, Konno H, and Barber GN. Ovarian cancer cells commonly exhibit defective STING signaling which affects sensitivity to viral oncolysis. Mol Cancer Res. (2019) 17:974–86. doi: 10.1158/1541-7786.MCR-18-0504
26. Hong SY, Cho A, Chae CS, and You HJ. Targeting ovarian neoplasms: subtypes and therapeutic options. Med (Kaunas). (2025) 61:2246. doi: 10.3390/medicina61122246
27. Shen M, Jiang X, Peng Q, Oyang L, Ren Z, Wang J, et al. The cGAS–STING pathway in cancer immunity: mechanisms, challenges, and therapeutic implications. J Hematol Oncol. (2025) 18:40. doi: 10.1186/s13045-025-01691-5
28. Li G, Zhao X, Zheng Z, Zhang H, Wu Y, Shen Y, et al. cGAS-STING pathway mediates activation of dendritic cell sensing of immunogenic tumors. Cell Mol Life Sci. (2024) 81:149. doi: 10.1007/s00018-024-05191-6
29. Bogani G, Moore KN, Ray-Coquard I, Lorusso D, Matulonis UA, Ledermann JA, et al. Incorporating immune checkpoint inhibitors in epithelial ovarian cancer. Gynecol Oncol. (2025) 193:30–40. doi: 10.1016/j.ygyno.2024.12.011
30. Chae YK, Othus M, Patel SP, Wilkinson KJ, Whitman-Purves EM, Lea J, et al. SWOG/NCI phase II dual anti-CTLA-4/PD-1 blockade in rare tumors: nonepithelial ovarian cancer. Clin Cancer Res. (2024) 30:5593–600. doi: 10.1158/1078-0432.CCR-24-0606
31. Ke H, Li Z, Li P, Ye S, Huang J, Hu T, et al. Dynamic heterogeneity of colorectal cancer during progression revealed clinical risk-associated cell types and regulations in single-cell resolution and spatial context. Gastroenterol Rep (Oxf). (2023) 11:goad034. doi: 10.1093/gastro/goad034
32. Friese C, Harbst K, Borch TH, Westergaard MCW, Pedersen M, Kverneland A, et al. CTLA-4 blockade boosts the expansion of tumor-reactive CD8(+) tumor-infiltrating lymphocytes in ovarian cancer. Sci Rep. (2020) 10:3914. doi: 10.1038/s41598-020-60738-4
33. Porter R, Bockorny B, Corr BR, Mahadevan D, Wilky BA, El-Khoueiry AB, et al. Botensilimab (Fc-enhanced anti-CTLA-4 antibody) plus balstilimab (anti-PD-1 antibody) in patients with treatment-refractory ovarian cancer. J Immunother Cancer. (2025) 13:e013222. doi: 10.1136/jitc-2025-013222
34. Pujade-Lauraine E, Fujiwara K, Ledermann JA, Oza AM, Kristeleit R, Ray-Coquard IL, et al. Avelumab alone or in combination with chemotherapy versus chemotherapy alone in platinum-resistant or platinum-refractory ovarian cancer (JAVELIN Ovarian 200): an open-label, three-arm, randomised, phase 3 study. Lancet Oncol. (2021) 22:1034–46. doi: 10.1016/S1470-2045(21)00216-3
35. Peng Z, Li M, Li H, and Gao Q. PD-1/PD-L1 immune checkpoint blockade in ovarian cancer: Dilemmas and opportunities. Drug Discov Today. (2023) 28:103666. doi: 10.1016/j.drudis.2023.103666
36. Miao X, Wang Z, Liu D, Ji S, Li J, and Zhang S. Exploring the application of PD-1/PD-L1 inhibitors for ovarian cancer. Cancer Treat Res Commun. (2025) 46:101053. doi: 10.1016/j.ctarc.2025.101053
37. 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
38. 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
39. Chen P, Pan J, Chen L, and Feng X. CIK-augmented anti-PD1/CTLA4 immunotherapy eradicates chemo-resistant ovarian cancer via tripartite mechanistic synergy. Front Oncol. (2025) 15:1670033. doi: 10.3389/fonc.2025.1670033
40. Pavicic PG Jr., Rayman PA, Swaidani S, Rupani A, Makarov V, Tannenbaum CS, et al. Immunotherapy with IL12 and PD1/CTLA4 inhibition is effective in advanced ovarian cancer and associates with reversal of myeloid cell-induced immunosuppression. Oncoimmunology. (2023) 12:2198185. doi: 10.1080/2162402X.2023.2198185
41. 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
42. Gao B, Carlino MS, Michael M, Underhill C, Marshall H, Gunjur A, et al. Nivolumab and ipilimumab combination treatment in advanced ovarian and endometrial clear cell cancers: A nonrandomized clinical trial. JAMA Oncol. (2025) 11:982–9. doi: 10.1001/jamaoncol.2025.1916
43. Wang X, He J, Ding G, Tang Y, and Wang Q. Overcoming resistance to PD-1 and CTLA-4 blockade mechanisms and therapeutic strategies. Front Immunol. (2025) 16:1688699. doi: 10.3389/fimmu.2025.1688699
44. Zhang S, Ke X, Zeng S, Wu M, Lou J, Wu L, et al. Analysis of CD8+ Treg cells in patients with ovarian cancer: a possible mechanism for immune impairment. Cell Mol Immunol. (2015) 12:580–91. doi: 10.1038/cmi.2015.57
45. He T, Zhang J, Zeng L, Yin Z, Yu B, Zhang X, et al. Composite score of PD-1 (+) CD8 (+) tumor-infiltrating lymphocytes and CD57 (+) CD8 (+) tumor ascites lymphocytes is associated with prognosis and tumor immune microenvironment of patients with advanced high-grade serous ovarian cancer. Chin J Cancer Res. (2025) 37:73–89. doi: 10.21147/j.issn.1000-9604.2025.01.06
46. Zhang Y, Cui Q, Xu M, Liu D, Yao S, and Chen M. Current advances in PD-1/PD-L1 blockade in recurrent epithelial ovarian cancer. Front Immunol. (2022) 13:901772. doi: 10.3389/fimmu.2022.901772
47. Hinchcliff EM, Knisely A, Adjei N, Fellman B, Yuan Y, Patel A, et al. Randomized phase 2 trial of tremelimumab and durvalumab in combination versus sequentially in recurrent platinum-resistant ovarian cancer. Cancer. (2024) 130:1061–71. doi: 10.1002/cncr.35126
48. Tan TJ, Sammons S, Im Y-H, She L, Mundy K, Bigelow R, et al. Phase II DORA study of olaparib with or without durvalumab as a chemotherapy-free maintenance strategy in platinum-pretreated advanced triple-negative breast cancer. Clin Cancer Res. (2024) 30:1240–7. doi: 10.1158/1078-0432.CCR-23-2513
49. Alizadeh D and Larmonier N. Chemotherapeutic targeting of cancer-induced immunosuppressive cells. Cancer Res. (2014) 74:2663–8. doi: 10.1158/0008-5472.CAN-14-0301
50. Li C, Qi X, and Yan M. Chemotherapy-induced immunogenic cell death in combination with ICIs: a brief review of mechanisms, clinical insights, and therapeutic implications. Front Pharmacol. (2025) 16:1572195. doi: 10.3389/fphar.2025.1572195
51. O’Cearbhaill RE, Homicsko K, Wolfer A, DiSilvestro PA, O’Malley DM, Sabbatini P, et al. A phase I/II study of chemo-immunotherapy with durvalumab (durva) and pegylated liposomal doxorubicin (PLD) in platinum-resistant recurrent ovarian cancer (PROC): Genomic sequencing and updated efficacy results. Gynecol Oncol. (2020) 159:41. doi: 10.1016/j.ygyno.2020.06.086
52. Monk BJ, Colombo N, Oza AM, Fujiwara K, Birrer MJ, Randall L, et al. Chemotherapy with or without avelumab followed by avelumab maintenance versus chemotherapy alone in patients with previously untreated epithelial ovarian cancer (JAVELIN Ovarian 100): an open-label, randomised, phase 3 trial. Lancet Oncol. (2021) 22:1275–89. doi: 10.1016/S1470-2045(21)00342-9
53. Drew Y, Kim JW, Penson RT, O’Malley DM, Parkinson C, Roxburgh P, et al. Olaparib plus Durvalumab, with or without Bevacizumab, as Treatment in PARP Inhibitor-Naïve Platinum-Sensitive Relapsed Ovarian Cancer: A Phase II Multi-Cohort Study. Clin Cancer Res. (2024) 30:50–62. doi: 10.1158/1078-0432.CCR-23-2249
54. Konstantinopoulos PA, Waggoner S, Vidal GA, Mita M, Moroney JW, Holloway R, et al. Single-arm phases 1 and 2 trial of niraparib in combination with pembrolizumab in patients with recurrent platinum-resistant ovarian carcinoma. JAMA Oncol. (2019) 5:1141–9. doi: 10.1001/jamaoncol.2019.1048
55. Randall LM, O’Malley DM, Monk BJ, Coleman RL, Gaillard S, Adams S, et al. Niraparib and dostarlimab for the treatment of recurrent platinum-resistant ovarian cancer: results of a Phase II study (MOONSTONE/GOG-3032). Gynecol Oncol. (2023) 178:161–9. doi: 10.1016/j.ygyno.2023.10.005
56. Sun J, Ren S, Zhao Q, He J, Wang Y, and Ren M. Endostatin-based anti-angiogenic therapy and immune modulation: mechanisms and synergistic potential in cancer treatment. Front Immunol. (2025) 16:1623859. doi: 10.3389/fimmu.2025.1623859
57. Hu H, Ma T, Liu N, Hong H, Yu L, Lyu D, et al. Immunotherapy checkpoints in ovarian cancer vasculogenic mimicry: Tumor immune microenvironments, and drugs. Int Immunopharmacol. (2022) 111:109116. doi: 10.1016/j.intimp.2022.109116
58. Moroney JW, Powderly J, Lieu CH, Bendell JC, Eckhardt SG, Chang CW, et al. Safety and clinical activity of atezolizumab plus bevacizumab in patients with ovarian cancer: A phase ib study. Clin Cancer Res. (2020) 26:5631–7. doi: 10.1158/1078-0432.CCR-20-0477
59. Liu JF, Herold C, Gray KP, Penson RT, Horowitz N, Konstantinopoulos PA, et al. Assessment of combined nivolumab and bevacizumab in relapsed ovarian cancer: A phase 2 clinical trial. JAMA Oncol. (2019) 5:1731–8. doi: 10.1001/jamaoncol.2019.3343
60. Lwin Z, Gomez-Roca C, Saada-Bouzid E, Yanez E, Muñoz FL, Im SA, et al. LBA41 LEAP-005: Phase II study of lenvatinib (len) plus pembrolizumab (pembro) in patients (pts) with previously treated advanced solid tumours. Ann Oncol. (2020) 31:S1170. doi: 10.1016/j.annonc.2020.08.2271
61. Lan CY, Zhao J, Yang F, Xiong Y, Li R, Huang Y, et al. Anlotinib combined with TQB2450 in patients with platinum-resistant or -refractory ovarian cancer: A multi-center, single-arm, phase 1b trial. Cell Rep Med. (2022) 3:100689. doi: 10.1016/j.xcrm.2022.100689
62. Alvarez Secord A, O’Malley DM, Sood AK, Westin SN, and Liu JF. Rationale for combination PARP inhibitor and antiangiogenic treatment in advanced epithelial ovarian cancer: A review. Gynecol Oncol. (2021) 162:482–95. doi: 10.1016/j.ygyno.2021.05.018
63. Liu J, Gaillard S, Hendrickson A, Moroney J, Yeku O, Diver E, et al. Samnotra VJS-SDhdoS-: An open-label phase II study of dostarlimab (TSR-042), bevacizumab (bev), and niraparib combination in patients (pts) with platinum-resistant ovarian cancer (PROC): Cohort A of the OPAL trial. Gynecologic Oncology (2021) 162:00680–6. doi: 10.1016/S0090-8258(21)00680-6
64. Zsiros E, Lynam S, Attwood KM, Wang C, Chilakapati S, Gomez EC, et al. Efficacy and safety of pembrolizumab in combination with bevacizumab and oral metronomic cyclophosphamide in the treatment of recurrent ovarian cancer: A phase 2 nonrandomized clinical trial. JAMA Oncol. (2021) 7:78–85. doi: 10.1001/jamaoncol.2020.5945
65. Kurtz JE, Pujade-Lauraine E, Oaknin A, Belin L, Leitner K, Cibula D, et al. Atezolizumab combined with bevacizumab and platinum-based therapy for platinum-sensitive ovarian cancer: placebo-controlled randomized phase III ATALANTE/ENGOT-ov29 trial. J Clin Oncol. (2023) 41:4768–78. doi: 10.1200/JCO.23.00529
66. 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
67. Harter P, Trillsch F, Okamoto A, Reuss A, Kim JW, Rubio-Pérez MJ, et al. Durvalumab with carboplatin/paclitaxel and bevacizumab followed by durvalumab and bevacizumab with or without olaparib maintenance in newly diagnosed non-BRCA-mutated advanced ovarian cancer. Ann Oncol. (2025). doi: 10.1016/j.annonc.2025.11.020
68. Xu C, Chen YP, Du XJ, Liu JQ, Huang CL, Chen L, et al. Comparative safety of immune checkpoint inhibitors in cancer: systematic review and network meta-analysis. Bmj. (2018) 363:k4226. doi: 10.1136/bmj.k4226
69. Borella F, Ghisoni E, Giannone G, Cosma S, Benedetto C, Valabrega G, et al. Immune checkpoint inhibitors in epithelial ovarian cancer: an overview on efficacy and future perspectives. Diagn (Basel). (2020) 10:146. doi: 10.3390/diagnostics10030146
70. Schneider BJ, Naidoo J, Santomasso BD, Lacchetti C, Adkins S, Anadkat M, et al. Management of immune-related adverse events in patients treated with immune checkpoint inhibitor therapy: ASCO guideline update. J Clin Oncol. (2021) 39:4073–126. doi: 10.1200/JCO.21.01440
71. Marabelle A, Fakih M, Lopez J, Shah M, Shapira-Frommer R, Nakagawa K, et al. Association of tumour mutational burden with outcomes in patients with advanced solid tumours treated with pembrolizumab: prospective biomarker analysis of the multicohort, open-label, phase 2 KEYNOTE-158 study. Lancet Oncol. (2020) 21:1353–65. doi: 10.1016/S1470-2045(20)30445-9
72. Marabelle A, Le DT, Ascierto PA, Di Giacomo AM, De Jesus-Acosta A, Delord JP, et al. Efficacy of pembrolizumab in patients with noncolorectal high microsatellite instability/mismatch repair-deficient cancer: results from the phase II KEYNOTE-158 study. J Clin Oncol. (2020) 38:1–10. doi: 10.1200/JCO.19.02105
73. Bamias A, Davis ID, Galsky MD, Arranz J, Kikuchi E, Grande E, et al. Atezolizumab monotherapy versus chemotherapy in untreated locally advanced or metastatic urothelial carcinoma (IMvigor130): final overall survival analysis from a randomised, controlled, phase 3 study. Lancet Oncol. (2024) 25:46–61. doi: 10.1016/S1470-2045(23)00539-9
74. Disis ML, Taylor MH, Kelly K, Beck JT, Gordon M, Moore KM, et al. Efficacy and safety of avelumab for patients with recurrent or refractory ovarian cancer: phase 1b results from the JAVELIN solid tumor trial. JAMA Oncol. (2019) 5:393–401. doi: 10.1001/jamaoncol.2018.6258
75. Mo DC and Ren T. Nivolumab versus gemcitabine or pegylated liposomal doxorubicin in patients with platinum-resistant ovarian cancer. J Clin Oncol. (2022) 40:522–3. doi: 10.1200/JCO.21.02208
76. Monk BJ, Colombo N, Tewari KS, Dubot C, Caceres MV, Hasegawa K, et al. First-line pembrolizumab + Chemotherapy versus placebo + Chemotherapy for persistent, recurrent, or metastatic cervical cancer: final overall survival results of KEYNOTE-826. J Clin Oncol. (2023) 41:5505–11. doi: 10.1200/JCO.23.00914
77. Liu Y, Xu H, van der Jeught K, Li Y, Liu S, Zhang L, et al. Somatic mutation of the cohesin complex subunit confers therapeutic vulnerabilities in cancer. J Clin Invest. (2018) 128:2951–65. doi: 10.1172/JCI98727
78. Landen CN, Molinero L, Hamidi H, Sehouli J, Miller A, Moore KN, et al. Influence of genomic landscape on cancer immunotherapy for newly diagnosed ovarian cancer: biomarker analyses from the IMagyn050 randomized clinical trial. Clin Cancer Res. (2023) 29:1698–707. doi: 10.1158/1078-0432.CCR-22-2032
79. Pignata S, Bookman M, Sehouli J, Miller A, Penson RT, Taskiran C, et al. Overall survival and patient-reported outcome results from the placebo-controlled randomized phase III IMagyn050/GOG 3015/ENGOT-OV39 trial of atezolizumab for newly diagnosed stage III/IV ovarian cancer. Gynecol Oncol. (2023) 177:20–31. doi: 10.1016/j.ygyno.2023.06.018
80. Al-Rawi DH, Rusk N, and Friedman CF. The search for genomic biomarkers of response to immunotherapy in ovarian cancer. Clin Cancer Res. (2023) 29:1645–7. doi: 10.1158/1078-0432.CCR-23-0048
81. Boland JL, Zhou Q, Martin M, Callahan MK, Konner J, O’Cearbhaill RE, et al. Early disease progression and treatment discontinuation in patients with advanced ovarian cancer receiving immune checkpoint blockade. Gynecol Oncol. (2019) 152:251–8. doi: 10.1016/j.ygyno.2018.11.025
Keywords: biomarker, chemotherapy, immune checkpoint inhibitor, ovarian cancer, PARP inhibitor, PD-1, tumor microenvironment
Citation: Yue S, Wen T, Liu X, Tang J, Liu Y and Peng S (2026) Overcoming immune resistance in ovarian cancer: checkpoint inhibitors, tumor microenvironment, and translational advances. Front. Oncol. 16:1762619. doi: 10.3389/fonc.2026.1762619
Received: 07 December 2025; Accepted: 16 January 2026; Revised: 09 January 2026;
Published: 05 February 2026.
Edited by:
Yunfei Liu, Central South University, ChinaReviewed by:
Chi Zhang, University of Texas MD Anderson Cancer Center, United StatesCopyright © 2026 Yue, Wen, Liu, Tang, Liu and Peng. 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: Shengxian Peng, MTMyNTgyODAzMTlAMTYzLmNvbQ==
†These authors have contributed equally to this work