Correction: Recent therapeutic advances in gynecologic oncology: evolving roles of immunotherapy, antibody–drug conjugates, and clinical trial innovations

Abstract

The occurrence of gynecologic cancers impacting the female reproductive system has been steadily rising, primarily due to modern lifestyle habits, unhealthy diets, and genetic predispositions [1]. These cancers encompass vulvar, uterine, vaginal, cervical, ovarian (OC), and fallopian-tube tumors, each classified according to anatomical origin. Fallopian-tube carcinoma remains exceptionally uncommon, accounting for less than 1% of female genital-tract malignancies [2,3]. In contrast, endometrial, ovarian, and cervical cancers are the most prevalent, together representing about 35-40% of cancers diagnosed in women worldwide [4]. Globally, cervical cancer ranks fourth among cancers in women, with approximately 604 000 new cases and 342 000 deaths in 2020, most occurring in low-and middle-income countries [5]. Endometrial (uterine) cancer is the sixth most common, causing roughly 417 000 cases and 97 000 deaths annually [6]. Ovarian cancer, often detected at advanced stages, ranks eighth, with 314 000 new cases and 207 000 deaths per year [7].Variations in incidence and mortality reflect access to screening, healthcare quality, reproductive behavior, and socioeconomic status [8]. These patterns underscore the global need for improved prevention, early detection, and individualized treatment strategies.The treatment of gynecologic cancers remains challenging, especially in advanced or recurrent disease [9]. Historically, carboplatin and paclitaxel have been the backbone of systemic therapy, acting through DNA cross-linking and microtubule stabilization, respectively [10]. However, resistance often develops due to enhanced DNA repair, survival-pathway activation, and altered drug metabolism [11]. Advances in molecular oncology and immunotherapy have revolutionized treatment paradigms by targeting tumor-specific mutations and immune-escape mechanisms. Agents such as bevacizumab (anti-angiogenic), PARP inhibitors (e.g., olaparib), and immune checkpoint inhibitors directed at PD-1/PD-L1 have become pivotal [12,13]. Bevacizumab received FDA approval in 2014 for ovarian cancer in platinum-resistant settings, while olaparib was first approved in 2014 for BRCA-mutated OC. Checkpoint inhibitors such as pembrolizumab were approved in 2017 for MSI-H or mismatch repair deficient (dMMR) solid tumors, including endometrial cancer. These therapies exemplify precision medicine by aligning treatment selection with molecular and immune biomarkers [14].Immune evasion constitutes a central obstacle to durable therapeutic response. The PD-1 receptor and its ligands PD-L1 and PD-L2 act as immune-checkpoint regulators that fine-tune T-cell activity and preserve peripheral tolerance (Figure 1) [15][16][17][18][19]. PD-L1 overexpression, observed in many gynecologic malignancies, enables tumor cells to bind PD-1 on activated T-cells and suppress immune cytotoxicity [18][19][20][21]. Blocking the PD-1/PD-L1 axis restores T-cell function, promotes tumor recognition, and enhances immune-mediated clearance [22]. High PD-L1 expression correlates with improved response to checkpoint blockade, establishing PD-L1 as a predictive biomarker for immunotherapy [23]. Ovarian, cervical, and endometrial cancers show frequent but variable PD-L1 expression [17].Ovarian cancers often display PD-L1 on both tumor cells and TAMs, whereas cervical tumors demonstrate high PD-L1 induction through HPV-related inflammation. Endometrial cancers, especially MSI-H or dMMR subtypes, exhibit strong PD-L1 expression associated with high T-cell infiltration. These differences influence responsiveness to PD-1 blockade and guide patient selection.Therapeutic antibodies targeting the PD-1/PD-L1 axis are primarily derived from IgG subclasses [24]. IgG1 antibodies can induce complement-dependent cytotoxicity (CDC) and antibody-dependent cellular cytotoxicity (ADCC), while IgG4 variants minimize these effects [25]. The IgG format selection balances immunostimulatory potential with safety [26]. Pembrolizumab (IgG4) was approved in 2017 for PD-L1-positive cervical cancer, and dostarlimab (IgG4) in 2021 for dMMR endometrial cancer, emphasizing their therapeutic value in gynecologic oncology.Recent years have seen a paradigm shift toward immune-based and biologically informed treatments. Pivotal trials-SHAPE, INTERLACE, KEYNOTE-A18, BEATcc, COMPASSION-16, NRG-GY018, RUBY, AtTEnd, DUO-E, LMS-04, PRIMA, DUO-O, ATHENA-combo, and FIRST-ENGOT-OV44-have redefined management across cervical, endometrial, and ovarian cancers [27,28]. Maintenance and combination regimens now incorporate PARP inhibitors, anti-angiogenic agents, and ICIs for improved survival and quality of life. The approval of niraparib (2019) as first-line maintenance in OC and lenvatinib plus pembrolizumab (2021) for advanced endometrial cancer set new standards of care. The DESTINY-PanTumor02 basket trial further validated trastuzumab deruxtecan for HER2-positive tumors, including gynecologic types. Molecular profiling and biomarker-guided stratification have enhanced precision oncology [27,28]. Trastuzumab deruxtecan, approved in 2022 for HER2-positive solid tumors irrespective of tissue origin, exemplifies antibody-drug conjugates (ADCs) transforming gynecologic oncology [18].Collectively, these developments mark a transition from conventional chemotherapy to biomarkerdriven immunotherapy and ADC approaches. The ongoing priorities are optimizing combination regimens, mitigating resistance, and extending these innovations to diverse histologic subtypes [19,29]. This review therefore examines current therapeutic advances in gynecologic oncology, emphasizing immunotherapy and ADC platforms that improve progression-free survival and reduce systemic toxicity in both early-stage and advanced disease. This narrative review followed a structured and transparent literature search to ensure clarity, reproducibility, and comprehensive coverage of recent advances in gynecologic oncology. The main goal was to examine recent progress in systemic therapy, focusing on immunotherapy and ADCs. A structured search strategy was designed that included database selection, keyword definition, and specific inclusion and exclusion criteria (Fig. 2). The process consisted of four phases: initial search, screening, eligibility assessment, and final inclusion. These stages were applied to identify peer-reviewed studies relevant to immunotherapy, ADCs, and targeted therapies in cervical, endometrial, and ovarian cancers. A total of 939 records were collected from PubMed, Scopus, Web of Science, ScienceDirect, Google Scholar, JSTOR, Science.gov, and the Bielefeld Academic Search Engine (BASE). After removing duplicates and unrelated records, 745 studies were reviewed by title, and 455 were evaluated by abstract and full text. In the final stage, 142 publications met the eligibility criteria and were included in the qualitative synthesis. Among these, 38 references were used to provide background information and methodological justification, while 104 supported the main analysis of therapeutic evidence and clinical outcomes.The search was conducted in February 2025 using combinations of the following keywords and Boolean operators: gynecologic oncology, cervical cancer, endometrial cancer, ovarian cancer, immune checkpoint inhibitors, PD-1, PD-L1, antibody-drug conjugates, trastuzumab deruxtecan, clinical trials, targeted therapy, and novel therapies. Only English-language, peer-reviewed publications from 2010 to 2025 were included. Editorials, letters, brief communications, and purely theoretical studies were excluded. Two independent reviewers evaluated each study for relevance and quality, and disagreements were resolved by consensus. ADCs have surfaced as a promising therapeutic approach in gynecologic oncology by selectively delivering potent cytotoxic agents to tumor cells while limiting off-target toxicity. In cervical cancer, the ADC tisotumab vedotin (TV) targeting tissue factor (TF) has gained FDA approval based on the innovaTV 204 trial, which showed durable responses in patients with recurrent or metastatic disease after standard chemotherapy failure. In endometrial cancer, agents such as trastuzumab deruxtecan targeting HER2 are under active investigation, especially in tumors with HER2 overexpression [30].Preliminary studies suggest these ADCs may work synergistically with immune checkpoint inhibitors in biomarker-selected subtypes of endometrial carcinoma. In OC, mirvetuximab soravtansine, which targets folate receptor alpha (FRα), has demonstrated encouraging clinical efficacy in platinumresistant cases. Based on results from the SORAYA trial, this ADC received accelerated FDA approval and is currently under evaluation in combination regimens [31,32].Across gynecologic malignancies, current ADCs differ in antigen targets, mechanisms, and payload types. For instance, TF, HER2, and FRα remain the principal targets, while monomethyl auristatin E (MMAE), exatecan, and DM4 are common cytotoxic warheads. Structurally, most agents are IgG1based conjugates with cleavable linkers. These distinctions, reflected in both approved and investigational compounds, underscore the importance of molecular profiling and tumor-specific antigen expression in optimizing ADC efficacy (Table 1). Early-stage cervical cancer, classified as FIGO 2009 stages IA1-IB1, comprises tumors confined to the cervix with limited local invasion [33]. Screening and HPV vaccination have substantially increased detection at these stages. The standard treatment has traditionally been radical hysterectomy, a procedure associated with considerable morbidity, including urinary, sexual, and bowel dysfunction caused by extensive parametrial dissection [34]. Because parametrial invasion occurs in less than 1% of tumors ≤2 cm, less aggressive surgery has been investigated to reduce treatment-related complications without compromising oncologic control [35].The SHAPE trial, a phase III randomized non-inferiority study, compared simple with radical hysterectomy in low-risk early-stage disease (IA2-IB1 < 2 cm, <10 mm stromal invasion, or <50% stromal involvement) (Table 2) [10,[33][34][35]. Among 700 patients, 3-year pelvic recurrence was 2.52% for simple versus 2.17% for radical hysterectomy (HR = 1.01; 95% CI 0.42-2.44). Patients undergoing simple hysterectomy experienced fewer urinary and sexual complications, demonstrating that de-escalation is feasible in appropriately selected patients [34][35][36][37]. Postoperative quality-of-life outcomes favored the simple hysterectomy group.Subsequent exploratory analyses indicated similar recurrence between minimally invasive and open simple hysterectomy (4.3% vs 5.3%) [37,38]; however, these comparisons were post-hoc. Earlier evidence from the LACC trial showed worse disease-free and overall survival (OS) for minimally invasive radical hysterectomy [38][39][40], emphasizing that surgical approach and patient selection remain critical. The ConCerv study further demonstrated that fertility-preserving conservative surgery can be safe in microinvasive disease ≤2 cm [39][40][41]. Collectively, SHAPE, LACC, and ConCerv trials highlight the current movement toward individualized, less invasive strategies in early-stage cervical cancer.While surgery continues to play an essential role, the therapeutic focus in cervical cancer is shifting toward molecularly informed and immune-based interventions. Immune checkpoint inhibitors such as pembrolizumab (anti-PD-1/PD-L1) and ADCs like TV have achieved meaningful responses in recurrent and metastatic settings and are being explored in neoadjuvant or adjuvant contexts [32].Their combination with targeted agents such as bevacizumab and PARP inhibitors may enhance efficacy and durability of response. Integrating these modalities into earlier disease stages could limit the need for extensive surgery or adjuvant chemoradiation, reducing long-term morbidity. [43]. In contrast, the ConCerv phase II multicenter trial evaluated conservative surgery in 100 women with stage IA2-IB1 (≤2 cm) tumors, node-negative and LVSI-negative, reporting a recurrence rate below 5% and supporting fertility-sparing surgery in selected low-risk patients [44].Collectively, findings from major trials including SHAPE, RTOG 0724/GOG-0724, SENTIX, LACC, and ConCerv demonstrate a consistent shift toward individualized and less invasive strategies in early-stage cervical cancer without compromising oncologic outcomes [45][46][47][48][49]. SHAPE confirmed the safety of simple hysterectomy in small-volume disease, while SENTIX validated SLN mapping as an alternative to full lymphadenectomy. Conversely, LACC underscored the limitations of MIS, and ConCerv strengthened evidence for conservative, fertility-preserving approaches. These studies emphasize precise patient selection based on tumor size, LVSI, and nodal status, alongside the integration of molecular and immune profiling to refine surgical decisions. Future directions involve combining minimally invasive and immunotherapy-based strategies, incorporating roboticassisted surgery, neoadjuvant immunomodulation, and patient-reported outcomes (PROs) to optimize long-term survival and quality of life [50,51]. Locally advanced cervical cancer (FIGO stages IB2-IVA) continues to pose a considerable clinical challenge even though concurrent chemoradiotherapy (CRT) is the established treatment. Survival rates level off around 60%, highlighting the necessity for increased therapy [49]. The main objectives of recent clinical trials in this context have been to enhance survival rates by incorporating systemic therapies like induction chemotherapy, immune checkpoint inhibitors, and adjuvant chemotherapy, to refine radiotherapy methods, and to pinpoint patient subgroups that could gain from personalized treatment intensification (Table 3). Additionally, there is an increasing emphasis on reducing longterm toxic effects and maintaining quality of life while attaining lasting disease management.A Here, abbreviations are as follows: CRT: chemoradiotherapy; VBT: vaginal brachytherapy; PFS: progression-free survival; OS: overall survival; TC: paclitaxel and carboplatin; RT: radiotherapy; PD-1: programmed cell death protein 1; CPS: combined positive score; HR: hazard ratio; IHC: immunohistochemistry; FDA: U.S. Food and Drug Administration; ADC: antibody-drug conjugate; MMAE: monomethyl auristatin E; HER2: human epidermal growth factor receptor 2; irAE: immunerelated adverse event.A complementary study, the CALLA trial, also assessed combining immunotherapy with CRT, but with different results [55]. This Phase III randomized double-blind trial involved patients with newly diagnosed FIGO 2009 stage IB2-IVA cervical cancer who received CRT plus either durvalumab (PD-L1 inhibitor) or placebo. No significant improvement in PFS was observed, despite a strong biological rationale for PD-L1 inhibition during CRT [55]. Possible contributing factors included a high proportion of stage IIIB cases, ethnic diversity, variable PD-L1 expression, and a short median follow-up (18.5 months), potentially limiting detection of long-term immunotherapy benefits [55].To better understand immunotherapy sequencing, the GOG-9929 trial investigated ipilimumab, a CTLA-4 inhibitor, given after CRT [56]. This Phase I/II non-randomized study enrolled patients with FIGO stage IB2-IIB node-positive cervical cancer. Patients received up to four doses of ipilimumab following CRT. The trial showed that sequential ipilimumab was safe and biologically active, with increased T-cell activation markers [56]. While not designed to measure survival outcomes, the trial provided key immunologic insights and laid the groundwork for ongoing studies on dual checkpoint blockade with CRT. Recent trials-including INTERLACE, KEYNOTE-A18, OUTBACK, CALLA, and GOG-9929-highlight evolving strategies for treating locally advanced cervical cancer, but also point to persistent challenges. Among the most promising results, INTERLACE demonstrated that induction chemotherapy before CRT significantly improved survival. A brief weekly paclitaxelcarboplatin regimen resulted in 5-year PFS of 72% versus 64% in the CRT-only group, and 5-year OS of 80% vs. 72% [57]. These outcomes support the rationale that tumor debulking enhances radiosensitivity and controls micrometastatic disease. The protocol's short duration and high compliance further strengthen its clinical utility.However, limitations of INTERLACE must be acknowledged. Participants were generally younger and healthier than typical real-world LACC patients [57]. In addition, many received 3D-CRT instead of IMRT, possibly underestimating the potential of modern radiotherapy [57]. The exclusion of patients with para-aortic nodal involvement also narrows its applicability. Building on intensification strategies, KEYNOTE-A18 marked a breakthrough by adding pembrolizumab to CRT [58]. It was the first Phase III trial to show a statistically significant OS benefit from integrating a PD-1 inhibitor into standard treatment for locally advanced cervical cancer. Patients receiving concurrent and maintenance pembrolizumab achieved a 3-year PFS of 69.3%, compared to 56.9% in the control group [58]. Other strengths included the use of advanced radiotherapy techniques and rapid global recruitment, supporting the generalizability of findings. However, several limitations must be considered. Despite the observed survival benefit, concerns remain about the cost and accessibility of pembrolizumab in low-and middle-income countries, where cervical cancer is most prevalent [58]. Additionally, subgroup analyses suggested greater benefit in non-White populations, though these findings should be interpreted with caution due to small sample sizes [58]. In contrast to these promising results, the OUTBACK trial illustrates the challenges of adjuvant chemotherapy after CRT [59]. Although the rationale for systemic intensification to eliminate micrometastases is strong, OUTBACK demonstrated no survival improvement with the addition of carboplatinpaclitaxel after CRT [59]. A major strength of the trial was its robust design and comprehensive follow-up, which confirmed that adjuvant cytotoxic chemotherapy offers no additional survival benefit after CRT.A supporting study, CALLA, also emphasized the complexities of combining immunotherapy with CRT [58]. Unlike KEYNOTE-A18, the CALLA trial, which evaluated durvalumab (a PD-L1 inhibitor) plus CRT, showed no statistically significant improvement in PFS. Nonetheless, CALLA's strengths included rigorous methodology and broad international representation, providing insights into real-world applicability [60]. It also highlighted potential limitations of PD-L1 blockade during CRT. Several factors may explain CALLA's lack of efficacy. First, the study included a higher proportion of FIGO stage IIIB patients, suggesting a greater tumor burden [58]. Second, PD-L1 expression was not used as a stratification factor, possibly including many patients less likely to respond. Lastly, the short median follow-up (18.5 months) may have been insufficient to capture delayed immunologic effects [52][53][54][55][56].Further investigation into sequencing strategies was explored in the GOG-9929 trial, which assessed ipilimumab (CTLA-4 inhibitor) after CRT. A key finding was the biological feasibility of this approach, shown by increased T-cell activation. Importantly, the safety profile was acceptable, with no unexpected immune-related toxicities. However, the non-randomized design and small sample size limit conclusions about clinical benefit. Without a comparator arm, it remains unclear whether immune activation translates to improved survival. Still, GOG-9929 laid the groundwork for current studies on dual checkpoint inhibition and optimal immunotherapy timing [27][28][29]. Taken together, these trials suggest key insights. Concurrent or maintenance immunotherapy appears more promising than adjuvant chemotherapy in LACC. The contrasting results of KEYNOTE-A18 (positive) and OUTBACK (negative) indicate that immunologic synergy during CRT is likely more effective than sequential cytotoxic therapy. Future trials should prioritize biomarker discovery-including PD-L1 expression, tumor mutational burden, and circulating tumor DNA-to enable more personalized treatments. Additionally, the cost-effectiveness and accessibility of therapies like pembrolizumab must be considered, especially in resource-limited settings [27,28].Crucially, trial design should reflect real-world complexities, including differences in tumor burden, radiotherapy access, and ethnic diversity. While KEYNOTE-A18 set a benchmark for global immunotherapy research, the negative outcomes of CALLA and OUTBACK have provided important lessons that will shape future directions [52]. In summary, recent trials in locally advanced cervical cancer have revealed both substantial progress and ongoing challenges. Lessons learned from INTERLACE, KEYNOTE-A18, OUTBACK, CALLA, and GOG-9929 now guide future research aimed at improving outcomes for women worldwide. Metastatic and recurring cervical cancer continues to pose a significant clinical challenge, with a history of restricted treatment options and low long-term survival rates. In the last ten years, though, the field has changed markedly with the integration of targeted treatments, ADCs, and immune checkpoint inhibitors. The key objectives of recent clinical trials have been to extend OS and PFS, implement new strategies for tumor management, and provide effective options for patients who have not responded to standard platinum-based chemotherapy. Numerous crucial studies-such as BEATcc, SKB264-II-06, COMPASSION-16, GOG-240, KEYNOTE-826, EMPOWER-Cervical 1, innovaTV 204, , and innovaTV-have transformed therapeutic approaches and offered significant understanding into refining systemic treatment for this high-risk group (Table 4).The BEATcc study stands as a significant phase III, randomized, open-label trial assessing the incorporation of atezolizumab, a PD-L1 inhibitor, into a chemotherapy and bevacizumab regimen for patients with metastatic, persistent, or recurrent cervical cancer [52]. Patients in the experimental group were given atezolizumab in combination with paclitaxel and either cisplatin or carboplatin, along with bevacizumab, every three weeks, whereas the control group excluded atezolizumab. Notably, the trial showed a marked enhancement in median PFS (13.7 vs. 10.4 months; HR=0.62; 95% CI=0.49-0.78; p<0.0001) and median OS (32.1 vs. 22.8 months; HR=0.68; 95% CI=0.52-0.88; p=0.0046) [52]. A key aspect that sets BEATcc apart from earlier trials is that PD-L1 status was not utilized as a selection criterion, thus expanding the relevance of the findings to a more diverse patient population [52].A further study adding to the growing therapeutic options is the SKB264-II-06 trial, a phase II, openlabel, basket trial examining the combination of sacituzumab-TMT (Sac-TMT) and pembrolizumab [53]. Focusing on patients who advanced after one or two lines of previous systemic treatment, this study indicated a 6-month PFS rate of 65.7% and an objective response rate (ORR) of 57.9% [53]. Despite being constrained by a modest sample size of 40 patients, SKB264-II-06 underscores the practicality and possible effectiveness of merging ADCs with immune checkpoint inhibitors in a challenging refractory environment. The EMPOWER-Cervical 1 trial strengthened the role of immunotherapy by testing cemiplimab monotherapy in the second-line setting [57]. This phase III, randomized, open-label study showed a significant OS benefit over chemotherapy (12.0 vs. 8.5 months; HR=0.69; 95% CI=0.56-0.84; p<0.001). As the first trial to prove a survival advantage with PD-1 monotherapy after platinum failure, EMPOWER-Cervical 1 expanded treatment options for pretreated patients. The innovaTV 204 trial introduced the potential of ADCs in cervical cancer [58]. This phase II, single-arm trial evaluated tisotumab vedotin, an ADC targeting tissue factor, in patients with prior chemotherapy. The trial reported an ORR of 24% and median OS of 12.1 months, with a manageable safety profile, supporting its role as a second-line option. These findings were validated by the innovaTV 301 study, a phase III, randomized, open-label trial comparing TV to investigator's choice chemotherapy [59].The trial confirmed a 30% reduction in mortality risk with TV (HR=0.70; p=0.0038) and established ADCs as a viable alternative to cytotoxic chemotherapy for heavily pretreated patients.Recent clinical trials such as BEATcc [52], KEYNOTE-826 [56], and COMPASSION-16 [54] have substantially advanced systemic therapy for metastatic and recurrent cervical cancer, confirming the pivotal role of immunotherapy in improving PFS and OS. The BEATcc study reported a median OS exceeding 32 months through the addition of atezolizumab to chemotherapy and bevacizumab, while KEYNOTE-826 established pembrolizumab-based regimens as the new standard for PD-L1-positive disease. Similarly, COMPASSION-16 demonstrated that cadonilimab, a dual PD-1 and CTLA-4 inhibitor, may offer clinical benefits for patients with PD-L1-negative tumors. Complementary evidence from GOG-240 [55] supported the integration of bevacizumab into combination therapy, and EMPOWER-Cervical 1 [57] confirmed the efficacy of cemiplimab monotherapy in platinumresistant settings. The introduction of ADCs such as TV in innovaTV 204 [58] and innovaTV 301 [59] trials further emphasizes the evolution toward personalized, biomarker-guided treatments. Despite these promising outcomes, several limitations persist, including patient selection bias toward PD-L1-positive or treatment-naïve populations, limited sample sizes in smaller studies such as SKB264-II-06 [53], and high treatment costs that hinder accessibility in low-and middle-income countries. Additionally, while ADCs like TV display acceptable safety profiles, ocular toxicities require careful monitoring, which may limit their widespread use. Collectively, these advances highlight a shift toward immune-based and targeted therapeutic strategies in cervical cancer, although broader validation and equitable global access remain critical challenges.In summary, although these crucial studies collectively indicate a significant change in the treatment of metastatic and recurrent cervical cancer, they also emphasize the necessity for ongoing improvement [60,61]. Upcoming trials must emphasize wider, real-world demographics to guarantee generalization, include cost-effectiveness evaluations to tackle global inequalities, and involve detailed biomarker stratification to enhance therapeutic advantages [62,63]. Furthermore, extended long-term monitoring is needed to evaluate the persistence of responses observed with immunotherapy and ADCs. As current studies advance from the achievements and insights of BEATcc, KEYNOTE-826, COMPASSION-16, and similar trials, a more personalized and attainable approach to cervical cancer treatment can be achieved, ultimately enhancing results for women globally [64][65]. ADCs have expanded options for recurrent or metastatic cervical cancer, where historical second-line chemotherapy produced modest response rates of 0-6% [66][67][68][69][70]. TV received regulatory approval based on the phase II innovaTV 204 trial, which reported an ORR of 24% among 102 previously treated patients and a median OS of 12.1 months [71,72]. Safety was manageable with characteristic ocular adverse events that require prophylaxis and monitoring [73,74]. The confirmatory phase III innovaTV 301 trial randomized 502 patients to TV versus investigator's choice chemotherapy and demonstrated improved outcomes with TV, including a 30% reduction in risk of death (HR 0.70; 95% CI 0.54-0.89) and longer PFS (HR 0.67; 95% CI 0.54-0.82) [75][76][77].Trastuzumab deruxtecan is an ADC for HER2-positive cervical cancer. In DESTINY-PanTumor02, the cervical cancer cohort (n=40) showed an ORR of 50% in a heavily pretreated population, supporting activity in this subgroup [73,78]. Based on these results, trastuzumab deruxtecan appears in the NCCN Compendium for recurrent HER2-positive disease, typically defined by IHC 2+ or 3+ [71].Together, TV and trastuzumab deruxtecan broaden the systemic therapy landscape in cervical cancer by providing effective options for unselected patients in the second-line setting (TV) and for HER2positive subsets (trastuzumab deruxtecan), with benefits shown in prospective trials [71,[73][74][75]78]. Endometrial cancer remains one of the most common gynecologic malignancies. While early-stage cases are often curable with surgery and adjuvant therapy, advanced or recurrent disease poses ongoing treatment challenges. Historically, platinum-based chemotherapy has been the standard of care; however, durable responses remain limited, particularly in patients with proficient mismatch repair (pMMR) tumors. In recent years, several phase III trials have redefined the therapeutic landscape by incorporating immune checkpoint inhibitors and targeted agents in both first-line and recurrent settings. Key studies-RUBY Part 1, NRG-GY018, AtTEnd, DUO-E, LEAP-001, ENGOT-en9/DUO-O, and TOTEM-have evaluated novel combinations aiming to improve PFS, OS, and sustained disease control across distinct molecular subtypes (Table 5). The RUBY Part 1 trial marked a major advance by evaluating dostarlimab, a PD-1 inhibitor, with carboplatin-paclitaxel in advanced or recurrent disease [79]. This randomized study showed significantly improved median PFS (11.8 vs. 7.9 months; HR=0.64; p<0.001) and a trend toward better OS (44.6 vs. 28.2 months; HR=0.69; p=0.002). Notably, the dMMR subgroup showed greater benefit (HR=0.28; p<0.001), emphasizing the importance of biomarker-based stratification. Inclusion of patients with carcinosarcomas broadened its applicability to aggressive histologies. The NRG-GY018 trial similarly tested pembrolizumab plus chemotherapy, stratifying patients by dMMR and pMMR status [80]. The trial reported significant PFS gains in both groups (dMMR HR=0.30, pMMR HR=0.54; both p<0.001), reinforcing the utility of checkpoint blockade across molecular profiles. In contrast to RUBY, carcinosarcomas were excluded, but the results still support pembrolizumab as a versatile immunotherapeutic agent. The AtTEnd trial assessed atezolizumab, a PD-L1 inhibitor, added to standard chemotherapy [81]. Although the improvement in PFS (10.1 vs. 8.9 months; HR=0.74, p=0.0022) was more modest, the study contributed supporting evidence for immunotherapy in this setting. Its inclusion of patients previously treated with chemotherapy (≥6 months interval) may explain the slightly attenuated outcomes. Ongoing OS analysis is needed to clarify long-term benefits.The DUO-E trial evaluated a maintenance strategy that integrated the PD-L1 inhibitor durvalumab with the PARP inhibitor olaparib after chemotherapy [82]. This immune-DNA repair co-targeting approach led to a significant PFS improvement (15.1 vs. 10.2 months; HR = 0.55; p < 0.0001) and a favorable OS trend (HR = 0.71; p = 0.003), underscoring the synergy between checkpoint inhibition and PARP-based DNA-damage modulation rather than PARP inhibitor monotherapy. In parallel, the LEAP-001 trial evaluated pembrolizumab with lenvatinib, a multi-tyrosine kinase inhibitor, as firstline therapy against chemotherapy [83]. This approach reflects growing interest in non-cytotoxic front-line regimens that integrate immunotherapy with targeted pathway inhibition.Although final noninferiority results are still awaited, initial data indicated that pembrolizumab combined with lenvatinib might provide similar efficacy to chemotherapy, especially in patients with biomarker-positive tumors [83]. This research represents a significant effort to incorporate chemotherapy-free protocols into initial treatment stages, with the goal of reducing long-term toxicity and improving patients' quality of life.A complementary investigation, ENGOT-en9/DUO-O, further examined first-line integration of durvalumab with chemotherapy and concurrent olaparib maintenance [84]. The trial focused on the dual-modality concept of combining immune checkpoint blockade with DNA-repair inhibition, rather than evaluating olaparib alone. The trial showed that incorporating olaparib with durvalumab and chemotherapy significantly extended PFS in patients with homologous recombination deficiency (HRD) and/or BRCA mutations (HR=0.42; p<0.0001) [84]. By concentrating on populations enriched at the molecular level, ENGOT-en9/DUO-O promotes the personalized treatment model, advocating for biomarker testing at diagnosis to enhance therapeutic stratification. Ultimately, the TOTEM study brought forth a completely novel category of treatment for endometrial cancer by exploring sacituzumab govitecan, which is an antibody-drug conjugate aimed at Trop-2 [85]. This phase II study revealed initial signs of effectiveness, with an ORR considerably exceeding expectations in a heavily pretreated population [85]. Although it is in the initial stages, the TOTEM study opens up possibilities for integrating ADCs into upcoming treatment regimens, enhancing the range of therapies accessible for recurrent disease. Endometrial cancer is among the most prevalent gynecologic cancers worldwide, and although earlystage cases typically show positive results after surgery and additional treatments, advanced or recurrent cases continue to pose a significant clinical hurdle. In recent years, there has been a significant change in the treatment of advanced and recurrent endometrial cancer due to the emergence of immunotherapy drugs, especially ICIs and ADCs [27,28]. These advancements are transforming treatment approaches by focusing on unique molecular pathways, providing renewed optimism for individuals with few alternatives. This review thoroughly details the key clinical trials and immunotherapeutic drugs that are transforming the treatment paradigm for endometrial cancer, incorporating data from significant studies and recent developments [29].Biomarkers have become key factors in determining the success of immunotherapy in endometrial cancer. The KEYNOTE-158 trial encompassed a cohort of endometrial cancer as well as a microsatellite instability-high (MSI-H)/dMMR population, revealing that pembrolizumab, a PD-1 blocker, demonstrated significant effectiveness in individuals with dMMR tumors [86]. In a study of 90 patients with MSI-H/dMMR endometrial cancer, 79 were assessable for efficacy, showing an ORR of 48%. The median PFS was 13.1 months, and there were lasting responses since the median OS was not attained [86]. This aligns with recent analyses highlighting the transformative role of ICIs in MMR-d/MSI-H endometrial cancer, where response rates range from 27% to 58% and integration with chemotherapy or TKIs is redefining standard-of-care strategies [87].Expanding on this, the authorization of pembrolizumab as a single agent paved the way for its use alongside conventional treatments. The NRG-GY018 trial assessed pembrolizumab alongside carboplatin and paclitaxel for patients with newly diagnosed advanced or recurrent endometrial cancer. Patients were categorized into dMMR and proficient MMR (pMMR) groups. In the dMMR cohort, the 12-month PFS was 74% for the pembrolizumab group versus 38% for the placebo group (HR=0.30; p<0.001), whereas in the pMMR group, median PFS increased to 13.1 months compared to 8.7 months (HR=0.54; p<0.001). These findings resulted in the inclusion of pembrolizumab alongside chemotherapy in the National Comprehensive Cancer Network (NCCN) guidelines as a Category I recommendation for stage III-IV endometrial cancer. Pembrolizumab's effectiveness was further enhanced when used alongside lenvatinib, a multitargeted tyrosine kinase inhibitor, in the KEYNOTE-775 trial. In recurrent pMMR advanced endometrial cancer that had been previously treated, the combination notably enhanced median PFS (6.6 vs. 3.8 months; HR=0.60; p<0.001) and OS (17.4 vs. 12.0 months; HR=0.68; p<0.001) when compared to the chemotherapy selected by the physician [88]. Considering the limited single-agent efficacy of pembrolizumab in pMMR tumors, the combination approach filled a significant treatment void, resulting in FDA approval in 2021 for pMMR advanced endometrial cancer following platinum treatment failure. Alongside pembrolizumab, dostarlimab has risen in prominence. Dostarlimab-gxly is a humanized IgG4 monoclonal antibody targeting anti-PD-1 that has shown significant efficacy in dMMR solid tumors. In the GARNET trial, a phase I study, dostarlimab demonstrated an ORR of 42.3% in patients with dMMR recurrent endometrial cancer, characterized by lasting responses and tolerable toxicity [89]. In light of these encouraging results, dostarlimab was granted accelerated FDA approval for dMMR recurrent endometrial cancer that advanced following platinum-based chemotherapy.The RUBY Part 1 trial reinforced dostarlimab's position in the frontline context. This phase III trial randomized patients with advanced or first recurrent endometrial cancer to receive dostarlimab with carboplatin-paclitaxel compared to placebo with chemotherapy [90]. The findings were striking: in the dMMR/MSI-H subgroup, the 24-month PFS stood at 61.4% compared to 15.7% (HR=0.28; p<0.001), and in the overall intent-to-treat group, PFS was likewise significantly extended (HR=0.64; p<0.001) [90]. As a result, dostarlimab in combination with chemotherapy was granted FDA approval in July 2023 for dMMR advanced or recurrent endometrial cancer, transforming frontline treatment.Another checkpoint inhibitor achieving notable progress is durvalumab, which inhibits PD-L1. In the DUO-E trial, durvalumab was examined alongside chemotherapy, followed by maintenance therapy that incorporated a PARP inhibitor (olaparib) in select biomarker-defined populations [91]. The study demonstrated that durvalumab-containing regimens achieved significant improvements in PFS compared with chemotherapy alone, particularly in patients exhibiting molecular signatures linked to DNA damage response. These findings highlight the potential of combining immune checkpoint inhibition with DNA repair pathway modulation, while avoiding emphasis on PARP monotherapy. Likewise, atezolizumab, a different PD-L1 inhibitor, has been assessed in the AtTEnd trial for advanced or initially recurrent endometrial cancer [92]. Interim analyses revealed enhanced median PFS with atezolizumab combined with chemotherapy versus placebo (HR=0.74; p=0.0219) [92]. In patients with dMMR particularly, the advantage was even more pronounced (HR=0.36; p=0.0219), indicating a notable efficacy driven by biomarkers. Final OS data are pending, however, these findings support the growing significance of PD-L1 blockade in endometrial cancer.Leveraging the achievements of trastuzumab, trastuzumab deruxtecan, an ADC that targets HER2, has exhibited encouraging efficacy in the DESTINY-PanTumor02 trial. In a preliminary analysis, the endometrial cancer group showed an ORR of 57.5%, a significant enhancement over historical controls receiving chemotherapy [94]. Furthermore, the STATICE trial broadened the use of trastuzumab deruxtecan for HER2-high and HER2-low uterine carcinosarcomas, reporting ORRs of 54.5% and 70%, respectively [95]. These results indicate that tumors exhibiting low HER2 expression could still gain considerable advantage, probably because of the bystander killing effect of trastuzumab deruxtecan. The treatment approach for endometrial cancer has increasingly focused on biomarkers. Testing for dMMR/MSI-H is now routine at diagnosis, influencing choices about immunotherapy eligibility. In a similar manner, HER2 testing guides the application of trastuzumab-containing regimens in serous histologies, while current research aims to enhance the role of PD-L1 expression, tumor mutational burden, and HRD status in personalizing therapies. Future directions focus on enhancing combination strategies to counteract resistance mechanisms. For instance, merging checkpoint inhibitors with agents that focus on angiogenesis (like lenvatinib), DNA damage repair mechanisms (such as olaparib), or additional immune checkpoints (including TIGIT, LAG-3 inhibitors) shows potential. Tailored methods that combine next-generation sequencing, circulating tumor DNA assessment, and ongoing biomarker tracking will enhance patient selection and treatment results.Overall, immunotherapy has significantly broadened the treatment options available for advanced and recurrent endometrial cancer. Medications like pembrolizumab, dostarlimab, durvalumab, atezolizumab, and new ADCs such as trastuzumab deruxtecan are transforming the standards of treatment. As more data becomes available from ongoing studies like DUO-E, AtTEnd, and DESTINY-PanTumor02, the incorporation of immunotherapy into first-line, maintenance, and recurrent contexts will progress further. The management of endometrial cancer in the future will focus on precision oncology, integrating molecular profiling, strategic drug development, and immunomodulation to attain lasting disease control and enhanced survival for every patient. OC remains the deadliest gynecologic malignancy, accounting for over 200,000 deaths annually worldwide. Most patients are diagnosed at FIGO stage III or IV, when the disease has already spread beyond the pelvis, and 5-year survival rates drop below 30% [45]. OC continues to be one of the most lethal gynecologic cancers, as most instances are identified at advanced stages. Even with improvements in surgical methods and chemotherapy based on platinum, the rates of recurrence continue to be elevated, and lasting remission is uncommon. In the last ten years, substantial work has been done to enhance results by incorporating targeted treatments, immune checkpoint blockers, and innovative maintenance approaches. A variety of clinical trials, including DUO-O, ATHENA Combo, PRIMA, NeoPembrOV, ANITA, ATALANTE, NRG-GY005, AGO-OVAR 2.29/ENGOT-ov34, LARA, BrUOG 354, and CARACO, have investigated innovative treatment alternatives (Table 6). These studies aim to enhance not only PFS and OS but also to improve patient stratification using molecular biomarkers like HRD and immune profiles. Together, these trials signify a move toward personalized treatment methods intended to enhance results for patients with locally advanced or recurrent OC, providing optimism for more efficient, lasting therapies beyond conventional cytotoxic methods [96].The DUO-O trial evaluated durvalumab (anti-PD-L1) and olaparib (PARP inhibitor) added to standard chemotherapy plus bevacizumab in newly diagnosed advanced OC. In this phase III study, maintenance with durvalumab + olaparib + bevacizumab significantly prolonged progression-free survival compared with bevacizumab alone (25.1 vs 19.3 months; HR 0.61, 95 % CI 0.51-0.73) [97].The benefit was greatest in HRD-positive tumors but extended across biomarker subgroups. DUO-O highlights synergy among PARP inhibition, immune checkpoint blockade, and angiogenesis suppression, underscoring the move toward biomarker-driven combination therapy in frontline OC. Here, ADC: antibody-drug conjugate; AE: adverse event; BEV: bevacizumab; CARB: carboplatin; CI: confidence interval; CRR: complete response rate; IDS: interval debulking surgery; HR: hazard ratio; ITT: intention-to-treat; IV: intravenous; mOS: median overall survival; mPFS: median progression-free survival; NR: not reached; OC: OC; ORR: objective response rate; OS: overall survival; PFS: progression-free survival; PLD: pegylated liposomal doxorubicin; TFI: treatment-free interval; TC: paclitaxel and car-boplatin; TFI: treatment-free interval.The ATHENA Combo trial assessed the combination of nivolumab (anti-PD-1) and rucaparib (PARP inhibitor) as maintenance therapy following platinum-based chemotherapy in newly diagnosed stage III-IV OC. This phase III, randomized, double-blind study enrolled 863 patients who had responded to first-line platinum treatment. The combination did not improve progression-free survival compared with rucaparib alone (15.0 vs 20.2 months; HR 1.29, 95 % CI 1.08-1.53) [98]. Although the results were negative, ATHENA Combo provided important insight into the complexity of integrating immune checkpoint blockade with DNA-damage repair inhibition. It underscored that not all combinations achieve additive benefit and highlighted the need for refined patient selection and biomarker-guided approaches to identify responders more precisely.The NeoPembrOV trial explored neoadjuvant chemoimmunotherapy by combining pembrolizumab (anti-PD-1) with standard platinum-taxane chemotherapy in patients with unresectable stage IIIC/IV high-grade serous or endometrioid OC. This phase II, randomized, open-label study compared pembrolizumab plus chemotherapy with chemotherapy alone, followed by interval debulking surgery and maintenance pembrolizumab. The addition of pembrolizumab was safe and feasible but did not significantly improve progression-free survival (19.4 vs 20.8 months) [100]. Despite the absence of clinical benefit in an unselected cohort, NeoPembrOV highlighted the importance of biomarkerguided patient selection and provided valuable evidence supporting the feasibility of introducing immunotherapy earlier in OC treatment.The ANITA trial evaluated atezolizumab (anti-PD-L1) in combination with platinum-doublet chemotherapy followed by niraparib (PARP inhibitor) maintenance in patients with platinum-sensitive recurrent OC. This phase III, randomized, double-blind study enrolled 417 participants with a treatment-free interval of at least six months. The combination produced a modest improvement in progression-free survival (11.2 vs 10.1 months) compared with the control arm [101]. Although the benefit was limited, ANITA confirmed the feasibility of combining immune checkpoint inhibitors with PARP inhibitors and anti-angiogenic agents in the recurrent setting. The trial underscored the importance of long-term safety monitoring and the optimization of combination dosing to balance efficacy and toxicity in multi-agent regimens.The ATALANTE trial investigated the addition of atezolizumab (anti-PD-L1) to carboplatin-based chemotherapy and bevacizumab maintenance in patients with platinum-sensitive recurrent nonmucinous epithelial OC. This phase III, randomized, double-blind trial included 614 participants with one or two prior treatment lines. The incorporation of atezolizumab resulted in a modest but statistically significant improvement in median progression-free survival (13.6 vs 11.3 months; HR 0.83, p=0.035) [102]. Although the clinical benefit was limited, ATALANTE reinforced the rationale for combining immune checkpoint blockade with anti-angiogenic therapy and underscored the need for more precise biomarker-based patient selection to identify subgroups most likely to benefit.The NRG-GY005 trial examined a non-chemotherapy combination of cediranib (VEGFR inhibitor) and olaparib (PARP inhibitor) versus standard chemotherapy in patients with platinum-resistant or refractory high-grade serous or endometrioid OC. This phase II/III, randomized, open-label study enrolled 562 participants and demonstrated a modest improvement in median progression-free survival (5.2 vs 4.3 months; HR 0.75) compared with chemotherapy [103]. While the benefit was limited, the trial provided important validation for chemotherapy-free strategies in heavily pretreated, resistant populations. NRG-GY005 emphasized the growing interest in integrating PARP inhibition with anti-angiogenic and immune-based approaches to expand therapeutic options for patients with few remaining treatment alternatives.The AGO-OVAR 2.29/ENGOT-ov34 trial evaluated the integration of atezolizumab (anti-PD-L1) with bevacizumab and chemotherapy in patients with recurrent platinum-sensitive high-grade OC. This phase III, randomized, double-blind study enrolled 574 participants to determine whether adding immune checkpoint blockade could enhance clinical outcomes. The inclusion of atezolizumab did not result in a statistically significant improvement in median progression-free survival (6.3 vs 6.6 months; HR 0.88) [104]. Despite the lack of clear efficacy, the trial provided valuable data on safety and treatment tolerability, reinforcing the importance of identifying biomarker-defined subgroups that could derive benefit from PD-L1 inhibition in combination with anti-angiogenic regimens.The LARA trial investigated the combination of pembrolizumab (anti-PD-1) and lenvatinib (tyrosine kinase inhibitor) in patients with recurrent clear cell OC or endometrial carcinoma. This phase II, open-label, two-stage study enrolled 27 patients and reported an ORR of 60% at 24 weeks [105].These findings highlight the therapeutic potential of combining immune checkpoint blockade with anti-angiogenic signaling inhibition in rare, chemoresistant histological subtypes. The trial underscores the growing importance of tailored immunotherapy approaches for molecularly distinct and aggressive OC variants, where conventional platinum-based regimens often yield limited benefit. The integration of ICIs, ADCs, and targeted combinations has transformed the treatment paradigm for gynecologic cancers, emphasizing biomarker-guided precision (Table 7). In cervical cancer, pembrolizumab in combination with platinum-taxane chemotherapy, with or without bevacizumab, represents a frontline standard for PD-L1-positive disease (KEYNOTE-826 [56]), while tisotumab vedotin (innovaTV 204/301 [58,59]) has established itself as a second-line ADC option targeting tissue factor (TF). Cemiplimab (EMPOWER-Cervical 1 [57]) further expanded immunotherapy indications to PD-L1-independent settings. Meanwhile, novel investigational combinations such as cadonilimab (dual PD-1/CTLA-4 blockade) and sacituzumab-TMT with pembrolizumab are exploring synergistic immune activation through complementary mechanisms like antigen release and immune cell priming. Collectively, these regimens illustrate how PD-1/PD-L1 blockade and ADC-based cytotoxic delivery are reshaping outcomes in both frontline and refractory disease contexts.In endometrial and ovarian cancers, ongoing advances underscore the growing role of multi-pathway synergy. In endometrial carcinoma, PD-1 inhibitors combined with chemotherapy or anti-angiogenic agents have achieved FDA/EMA approval across molecular subtypes, including pembrolizumab plus carboplatin/paclitaxel (NRG-GY018 [87]), dostarlimab plus chemotherapy (RUBY Part 1 [90]), and pembrolizumab plus lenvatinib (KEYNOTE-775 [88]), now standard for pMMR disease. The addition of durvalumab with PARP inhibition (DUO-E [91]) and early ADC strategies (TOTEM [94,95]) reflect future directions toward integrated, biomarker-driven regimens. In ovarian cancer, immunotherapy remains investigational but promising, with triplet combinations like durvalumab + olaparib + bevacizumab (DUO-O [97]) showing synergistic potential through DNA-damage accumulation and immune activation. Although other trials (ATHENA Combo, ANITA, ATALANTE) yielded modest or negative results, exploratory regimens such as pembrolizumab + lenvatinib and nivolumab ± ipilimumab in clear cell subtypes highlight the ongoing refinement of immunologic and molecularly tailored strategies. Together, these findings consolidate a unified framework for precision immunotherapy across gynecologic malignancies, balancing established standards with emerging targeted innovations.In ovarian cancer, the therapeutic landscape is undergoing a steady evolution toward rationally designed combinations that leverage DNA repair targeting, angiogenesis modulation, and immune activation. While immune checkpoint inhibitors alone have shown limited efficacy in unselected populations, combining them with PARP inhibitors and anti-angiogenic agents has yielded promising signals in biomarker-defined subgroups. The DUO-O trial [97] exemplifies this progress, demonstrating that the addition of durvalumab and olaparib to standard bevacizumab maintenance significantly prolonged progression-free survival, particularly in HRD-positive tumors. This triplet approach capitalizes on complementary mechanisms: PARP inhibition induces DNA damage and neoantigen release, VEGF blockade improves immune infiltration, and PD-L1 inhibition reactivates exhausted T cells. Other investigations, such as ANITA [101] and ATALANTE [102], have validated the biological rationale for integrating PD-L1 blockade with PARP inhibitors and anti-angiogenic therapy, though their clinical gains were modest. Novel chemo-free strategies, including cediranib plus olaparib (NRG-GY005 [103]), further illustrate the pursuit of durable, less toxic regimens for platinum-resistant disease. Importantly, rare and chemoresistant histotypes like clear cell ovarian carcinoma are emerging as distinct immunogenic subgroups responsive to dual checkpoint blockade or PD-1-TKI combinations, as shown in LARA [105] and BrUOG 354 [106]. Overall, these findings underscore a shift from conventional cytotoxic therapy toward integrated, molecularly informed regimens that aim to achieve sustained disease control through multi-target immune modulation. Artificial intelligence (AI) is increasingly being applied across gynecologic oncology to enhance precision medicine by integrating genomic, proteomic, and clinical data [108]. Early frameworks such as the MIA3G and MCF models demonstrated how multi-parameter learning systems can stratify OC risk and improve diagnostic accuracy using combinations of biomarkers like CA125, HE4, and β₂-microglobulin [109,130]. These approaches achieved high sensitivity and specificity in retrospective datasets and highlighted the capacity of AI to extract non-linear diagnostic patterns beyond traditional statistical models [110][111][112]. Despite these advances, interpretability and limited external validation remain challenges, emphasizing the need for explainable AI (XAI) and prospective, multi-institutional verification (Table 8) [113][114][115][116][117][118][119]. AI methodologies have also been introduced into surgical oncology for risk assessment and perioperative optimization. Machine-learning models such as XGBoost, random-forest, and deeplearning frameworks predict cytoreductive outcomes, postoperative morbidity, and intensive-care needs by analyzing clinical and imaging data [113][114][115][116][117][118][119][120][121]. These models identify key variables including diaphragm and bowel involvement or estimated blood loss, which aid intraoperative decision-making and improve surgical planning [122][123][124]. Comparable tools have been developed for endometrial and cervical cancers, integrating metabolomic or radiologic data to predict parametrial invasion and survival outcomes [125][126][127][128]. Collectively, these algorithms exemplify AI's capacity to personalize surgical strategies and reduce complications.Recent investigations have broadened AI's role in molecular prediction. Models integrating circulating-free DNA (cfDNA), metabolomic profiles, and multi-omics features enhance early detection of OC and uterine corpus endometrial carcinoma (UCEC) [129][130][131][132][133][134][135][136][137][138][139][140][141]. Frameworks such as DELFI, based on cfDNA fragmentomics, and GC-MS-based metabolomic classifiers demonstrated robust AUC values and accuracy exceeding 90%, underscoring AI's diagnostic strength for minimally invasive screening [134][135][136][137][138][139]. However, dataset heterogeneity, population bias, and lack of standardized analytic pipelines still constrain clinical translation.Beyond diagnostics and surgical optimization, artificial intelligence can play a transformative role in integrating immunotherapy and ADCs into the therapeutic continuum of gynecologic malignancies. Machine learning models could identify predictive immune signatures such as PD-L1 expression patterns, tumor mutational burden, microsatellite instability, and immune cell infiltration to guide patient selection for checkpoint blockade therapies. Similarly, AI-driven multi-omics integration could uncover molecular determinants of ADC response, including HER2 expression, receptor density, and intracellular trafficking efficiency, thereby improving target validation and therapeutic precision. Advanced predictive frameworks may also enable dynamic treatment adaptation by correlating radiomic or liquid biopsy data with immune response kinetics, helping clinicians anticipate resistance or toxicity in real time. In the long term, explainable AI systems combining genomic, proteomic, and histopathologic data could serve as clinical decision-support tools, harmonizing the use of immunotherapy and ADCs within personalized gynecologic oncology treatment algorithms (Figure 3). While the reviewed studies demonstrate considerable promise, significant challenges endure. Numerous investigations rely on retrospective data or narrowly defined cohorts, which may restrict external validity. Additionally, the regulatory frameworks for AI-driven diagnostics are still in nascent stages, necessitating the establishment of harmonized standards for validation, transparency, and clinical incorporation. Lastly, the interpretability of AI models is a pivotal concern in clinical environments, where explainable AI (XAI) could significantly facilitate clinician acceptance [142].Future investigations must prioritize prospective, multicenter validation, encompass diverse ethnic groups, and include cost-effectiveness evaluations to guarantee equitable implementation. Furthermore, the synergy with multi-omics data (genomics, transcriptomics, metabolomics, and proteomics) could lead to the development of highly personalized and robust diagnostic instruments that surpass existing biomarker constraints. Promising but still investigational options include multi-agent combinations such as durvalumab with olaparib (DUO-E), atezolizumab-based chemoimmunotherapy (ATALANTE, ANITA), and nextgeneration ADCs including trastuzumab deruxtecan and sacituzumab govitecan. These regimens show encouraging activity but require extended follow-up and biomarker validation before full clinical endorsement. Artificial-intelligence-assisted clinical decision models and surgical outcome prediction tools also belong to this emerging category. Although their early performance is strong, broader validation is needed before routine use in perioperative care.Approaches that currently lack clear clinical benefit include PARP inhibitor-immunotherapy combinations without biomarker selection such as ATHENA Combo and NeoPembrOV. Their limited synergy illustrates the importance of rational trial design based on immune profiling, DNA repair status, and tumor microenvironment biology rather than empirical combination.Future work should focus on refining predictive biomarkers such as HRD, MSI-H/dMMR, PD-L1, and HER2 expression and integrating them into clinical algorithms. The use of genomic, proteomic, and radiomic data analyzed through transparent AI models may help optimize patient selection and anticipate resistance. Equal attention should be given to cost-effectiveness and access to high-value therapies in resource-limited regions.In summary, gynecologic oncology is rapidly moving from empiric therapy toward precision-based treatment. Immunotherapy and ADCs now represent standards for biomarker-defined patient groups, while combination strategies and AI-assisted approaches continue to evolve. Progress will depend on multidisciplinary collaboration, innovative trial design, and harmonized biomarker testing to ensure that advances in precision medicine translate into better survival and quality of life for women worldwide.