Search Results (901)

Cholangiocarcinoma (CCA) is an aggressive and molecularly heterogeneous malignancy characterized by a profoundly immunosuppressive tumor microenvironment (TME) and historically limited therapeutic options. Recent advances have redefined the treatment paradigm, with phase III trials establishing chemoimmunotherapy as a standard of care and multi-omic profiling elucidating the interplay between tumor genomics, stromal architecture, and immune regulation. Despite these gains, durable clinical benefit remains confined to a minority of patients, reflecting convergent mechanisms of primary and acquired resistance—including immune exclusion, myeloid-dominant suppression, and genotype-driven “cold” tumor states. In this review, we synthesize emerging insights into the immune landscape of CCA, integrating data from single-cell, spatial, and translational studies to define the cellular and molecular circuits governing immune evasion. Beyond canonical biomarkers such as mismatch repair and microsatellite status, we highlight how spatial organization of immunity—in particular, tertiary lymphoid structures, dynamic myeloid and stromal interactions, and pathway-level features—shape immunotherapy responsiveness. We also examine how tumor-intrinsic alterations, including IDH1 mutation, FGFR2 fusions, KRAS activation, and MTAP loss, define distinct immunologic phenotypes with direct implications for immunotherapeutic response and biomarker-driven patient selection. We evaluate the expanding clinical trial landscape of immunotherapy in CCA and more broadly in BTC, including adoptive cell therapies and cancer vaccines. Together, these advances position CCA as a paradigm of how tumor genotype and microenvironment co-evolve to define immunotherapy sensitivity and resistance. Full article

Melanoma has long represented a unique challenge in oncology. In its early stages, it can often be cured with surgery alone, resulting in excellent survival outcomes. Its biology is complex and heterogeneous, often including mutations such as BRAF and NRAS, which partly explain its high immunogenicity but also its capacity to relapse. For many decades, the standard approach in resectable stage III melanoma was surgery first, followed by adjuvant therapy. In the last decade, the development of immune checkpoint inhibitors created the opportunity to treat patients before surgery. The neoadjuvant approach is based on the hypothesis that treatment of the intact tumor may enhance antitumor immune priming and activation. The first prospective neoadjuvant studies, including OpACIN and OpACIN-neo, showed high pathological response rates with ipilimumab plus nivolumab and introduced pathological response as an early marker of long-term benefit. The PRADO study showed that treatment response could guide the extent of surgery required. The SWOG S1801 trial demonstrated better event-free survival with perioperative pembrolizumab compared to adjuvant therapy alone. Lastly, the phase III NADINA trial showed that neoadjuvant ipilimumab plus nivolumab followed by response-adapted adjuvant therapy significantly improves outcomes. Biomarkers such as PD-L1, IFN-γ signature, tumor mutational burden and imaging (PET scan) appear promising to predict response, but none have been sufficiently validated for routine clinical practice. Full article

Background: Programmed death-1 (PD-1) inhibitors have significantly improved survival outcomes in melanoma; however, questions persist regarding comparative efficacy across regimens and the predictive value of PD-L1 expression as a biomarker. We therefore performed a meta-analysis evaluating outcomes according to PD-L1 expression status using the most recent follow-up data from each study. Methods: A systematic search was conducted in PubMed, Cochrane and ClinicalTrials.gov from 1 January 2010 to 1 April 2025 for phase II and III randomized clinical trials (RCTs) investigating PD-1 inhibitors as monotherapy or combined with other immune checkpoint inhibitors (ICIs) or targeted therapy in the adjuvant/metastatic setting. Pooled estimates were calculated with random-effects models, and risk of bias was assessed using the Cochrane RoB 2 tool. The present meta-analysis was performed following PRISMA guidelines and was registered in PROSPERO (ID: CRD420251090090). Results: Fifteen RCTs including 9979 patients were included. In the overall analysis, PD-1 inhibitors were associated with significantly improved overall survival (OS, HR = 0.75, 95% CI: 0.66–0.86) compared with control treatments. In the unresectable or metastatic setting, progression-free survival (PFS) was also significantly improved (HR = 0.61, 95% CI: 0.49–0.76). Survival benefits were observed in both PD-L1-positive and PD-L1-negative tumors, with improved PFS in PD-L1-positive (HR = 0.63, 95% CI: 0.48–0.83) and PD-L1-negative patients (HR = 0.58, 95% CI: 0.44–0.77), as well as improved OS in PD-L1-positive (HR = 0.69, 95% CI: 0.59–0.80) and PD-L1-negative patients (HR = 0.79, 95% CI: 0.67–0.93), without evidence of effect modification by PD-L1 expression. PD-1 inhibitor-based regimens were not associated with a statistically significant increase in grade 3–4 treatment-related adverse events (RR = 1.13, 95% CI: 0.71–1.79); however, heterogeneity was substantial (I² = 96.0%). Conclusions: PD-1 inhibitor-based therapies significantly improve survival outcomes in advanced melanoma across PD-L1 subgroups. No clear evidence of differential treatment benefit according to PD-L1 expression was observed, suggesting limited utility as a standalone predictive biomarker. Further studies integrating molecular and immune profiling are warranted to optimize individualized treatment selection. Full article

Background: Penetrating keratoplasty (PK) is a technically demanding corneal transplant procedure frequently performed in elderly patients with substantial systemic comorbidities. In this population, an anesthetic strategy that ensures hemodynamic stability, cooperative sedation, adequate analgesia, and preserved spontaneous ventilation is highly desirable. Dexmedetomidine, a highly selective alpha2-adrenergic agonist, provides “cooperative” sedation with minimal risk of respiratory depression and additional sympatholytic benefits. Methods: This single-center retrospective observational case series included 50 consecutive patients (American Society of Anesthesiologists [ASA] II–III, age 50–90 years) undergoing PK under sub-Tenon block combined with continuous dexmedetomidine infusion. Dexmedetomidine was administered without a loading bolus at 0.7 mcg/kg/h for 10–15 min, then reduced to 0.5 mcg/kg/h, targeting a Ramsay Sedation Scale (RSS) score of 2–3. The sub-Tenon block was performed using a mixture of levobupivacaine 0.5% and lidocaine 2% (3–5 mL). Heart rate (HR), mean arterial pressure (MAP), oxygen saturation (SpO₂) and RSS were recorded in nine predefined perioperative phases. Data were analyzed descriptively. Results: The mean age was 72 ± 9 years; 52% of patients were ASA III. Hypertension was present in all patients; 30% had cardiovascular disease, 28% diabetes mellitus type II, and 30% chronic obstructive pulmonary disease. Progressive, controlled bradycardia was observed (mean HR decreased from 76 to 57 beats/min during graft transplantation), while MAP gradually decreased from hypertensive baseline values (150–160 mmHg) to an optimal intraoperative range of 115–130 mmHg, without episodes of clinically significant hypotension. SpO₂ remained stable at 98–99% throughout all phases, with no episodes of desaturation or need for airway intervention or supplemental oxygen. Target sedation (RSS 2–3) was achieved in all patients (median RSS 3), with preserved spontaneous breathing and cooperation. Sub-Tenon block-related bulging occurred in 6% of cases. No episodes of clinically significant bradycardia, malignant arrhythmia, respiratory compromise, or need to discontinue dexmedetomidine were recorded. No opioids or non-steroidal analgesics were required intraoperatively or in the early postoperative period. Conclusions: The combination of sub-Tenon block and continuous dexmedetomidine sedation without a loading bolus represents a hemodynamically stable and respiratory-safe anesthetic strategy for PK in elderly, high-risk patients. These preliminary, hypothesis-generating findings suggest that the protocol provides stable surgical conditions and a favorable safety profile, justifying future prospective randomized controlled trials to establish its comparative efficacy against general anesthesia or standard sedative regimens. Full article

Background: The therapeutic landscape of metastatic prostate cancer has rapidly evolved with the integration of biomarker-driven strategies, particularly targeting homologous recombination repair (HRR) alterations. Poly(ADP-ribose) polymerase inhibitors (PARPi) have demonstrated clinically meaningful benefit, especially in Breast Cancer genes 1/2-altered tumors, through synthetic lethality. However, the expansion of PARPi across multiple Treatment settings has introduced substantial complexity in patient selection, Treatment sequencing, and biomarker interpretation. This review aims to move beyond a descriptive synthesis of clinical trials and provide a clinically applicable, decision-oriented framework for the use of PARP inhibitors in metastatic prostate cancer. Methods: We conducted a narrative review of pivotal phase II and III trials published between 2020 and 2026 evaluating PARPi as monotherapy or in combination strategies. Evidence was critically analyzed with a focus on biomarker relevance, Treatment positioning, and real-world applicability. Evidence Synthesis: PARPi consistently improve radiographic progression-free survival, with the most robust and clinically meaningful benefit observed in BRCA-altered disease. In contrast, non-BRCA HRR alterations demonstrate heterogeneous and often limited predictive value, highlighting the limitations of a binary biomarker approach. Combination strategies in first-line metastatic castration-resistant prostate cancer (mCRPC) have expanded therapeutic options but raise important concerns regarding toxicity, overTreatment, and unclear benefit in biomarker-unselected populations. In parallel, variability in molecular testing strategies and access continues to limit real-world implementation. Conclusions: PARP inhibitors represent a cornerstone of precision oncology in metastatic prostate cancer, but their optimal use requires a refined, biomarker-informed approach. In this context, we propose a pragmatic 2026 clinical decision framework integrating molecular characteristics, prior Treatment exposure, and clinical factors. This approach aims to bridge the gap between clinical trial evidence, guideline recommendations, and real-world practice. Full article

Sarcoidosis is a multisystem granulomatous disorder of uncertain origin which still presents major therapeutic dilemmas. Longstanding dependence on corticosteroids, while effective for acute inflammation, carries considerable adverse effects over time. Advances in deciphering sarcoidosis pathobiology—including aberrant Janus kinase (JAK)- signal transducer and activator of transcription (STAT) signaling, mechanistic target of rapamycin (mTOR)-driven metabolic shifts, Th1/Th17.1 immune skewing, effector T-cell exhaustion, and granuloma-centered cytokine circuits—have revealed several targets for intervention. The treatment options are rapidly changing: the SARCORT trial showed that low-dose prednisolone is non-inferior to higher prednisolone doses; the pivotal PREDMETH trial validated methotrexate as a feasible first-line steroid-sparing option; efzofitimod, a novel immunomodulator targeting neuropilin-2, produced steroid-reducing effects in Phase IIbut not in Phase III trials; and JAK inhibitors are accumulating evidence across cutaneous and systemic presentations. The 2025 World Association for Sarcoidosis and Other Granulomatoses (WASOG) statement supports a move toward earlier steroid-sparing approaches. This review methodically connects sarcoidosis molecular and pathophysiological mechanisms to new targeted treatments, examines clinical trial evidence, and proposes future directions toward biomarker-driven individualized care. Full article

Background: Venous thromboembolism (VTE) remains a clinically relevant complication following major orthopaedic procedures, particularly total hip arthroplasty (THA), total knee arthroplasty (TKA), and fracture surgery. Although low-molecular-weight heparin (LMWH) and direct oral anticoagulants (DOACs) are widely regarded as standard pharmacological options, aspirin (acetylsalicylic acid, ASA) has gained renewed attention because of its low cost, oral administration, and favourable bleeding profile. However, the available evidence is heterogeneous, and its interpretation is complicated by differences in patient selection, timing and duration of prophylaxis, diagnostic methodology, aspirin dosing regimens, and the increasing adoption of modern fast-track arthroplasty pathways. Methods: A structured evidence-based review was conducted in accordance with PRISMA 2020 principles. PubMed, Embase, Web of Science, and the Cochrane Library were searched through September 2025 for randomised controlled trials (RCTs), major international clinical practice guidelines, and selected high-level studies relevant to the interpretation of aspirin-based orthopaedic thromboprophylaxis. Nine RCTs, four major guideline documents, and sixteen additional Level I–II studies were included. Outcomes of interest were symptomatic deep vein thrombosis (DVT), pulmonary embolism (PE), major bleeding, and mortality. Risk of bias was assessed using the Cochrane ROB 2 framework. Owing to marked methodological heterogeneity, no formal pooled meta-analysis was undertaken. Results: The available RCT evidence suggests that aspirin may perform adequately within structured sequential or risk-stratified prophylaxis strategies, but not in all clinical settings. In arthroplasty, EPCAT II demonstrated non-inferiority of aspirin when introduced after an initial five-day course of rivaroxaban, whereas CRISTAL showed higher early symptomatic VTE rates when aspirin was used as sole primary prophylaxis from postoperative day 0. Importantly, thromboembolic events in CRISTAL occurred earlier in the aspirin cohort, supporting the concept that anticoagulant therapy remains important during the immediate postoperative hypercoagulable phase. In trauma surgery, PREVENT CLOT established non-inferiority of aspirin compared with LMWH for 90-day mortality; however, the predominantly young study population and the inclusion of upper-extremity fractures limit extrapolation to elderly hip fracture patients. Several smaller RCTs reported no major differences between aspirin and anticoagulants, but these studies were frequently underpowered and relied on less sensitive diagnostic strategies. Historical and contemporary guidelines remain heterogeneous, and evidence from modern fast-track arthroplasty pathways suggests that current trial-based conclusions may not be directly generalisable to short-duration prophylaxis settings. Conclusions: Aspirin may have a role in orthopaedic thromboprophylaxis when used within structured, risk-adapted or sequential protocols, particularly in standard-risk arthroplasty patients and selected trauma populations. However, current evidence does not support its universal use as sole primary prophylaxis in major orthopaedic surgery, especially during the early postoperative hypercoagulable phase or in high-risk patients. Furthermore, the available literature does not permit definitive recommendations regarding the optimal aspirin dose or duration of prophylaxis. The generalisability of the existing literature is further limited by methodological heterogeneity and by the absence of RCTs directly evaluating ultra-short anticoagulant regimens versus prolonged aspirin prophylaxis in modern fast-track arthroplasty. Further high-quality, standardised trials are required. Full article

Drug repurposing is often promoted as a faster, lower-risk alternative to de novo discovery, yet substantial barriers continue to limit successful implementation. We performed a scoping review of articles included in PubMed and ScienceDirect with the aim to identify and categorize challenges and analyze the intersections between them. Our review included 73 articles which revealed scientific, clinical, regulatory, economic, and implementation barriers, with the principal being the clinical translation of generated candidates. Scientific challenges include the necessity for new Phase II/III trials to validate efficacy, safety, and optimal dosing in new therapeutic contexts. Across disease areas, domain-specific barriers include subgroup-dependent responses in oncology, resistance and penetration challenges in anti-infectives, and data scarcity in rare diseases. Computational and AI-assisted approaches face fragmented data, model robustness, and insufficient validation. In addition, off-patent drugs face evidence requirements as rigorous as those for de novo entities, yet lack the market exclusivity incentives required to attract private investment. Additionally, an “institutional bottleneck” hinders academic researchers from bringing findings “on-label” due to a lack of regulatory infrastructure and collaborative frameworks. We conclude that drug repurposing requires a distinct translational paradigm involving multi-stakeholder collaboration and early regulatory engagement to bridge the gap between laboratory discovery and patient access. Full article

Background: Idiopathic pulmonary fibrosis (IPF) is an incurable disease with limited therapeutic options and a poor prognosis. Current standard therapies are characterized by drugs or surgical strategies with limited effects, as they are either not curative or their use is restricted to a specific subset of the population. The aim of this scoping review is to evaluate the drugs currently under investigation in Phase II and Phase III trials and provide an overview of the mechanisms of new therapeutic strategies for IPF. Methods: The search strategy was conducted in accordance with PRISMA guidelines and included studies conducted on adults with IPF retrieved from the registered ClinicalTrials.gov database up to 31 December 2025. Results: Nineteen studies were included. The clinical trials investigate key signaling pathways and molecular targets, including MAPK, RhoA/ROCK, PDE4B/cAMP, Wnt/β-catenin, Hedgehog/SMO, IL-11/STAT3, and LPA/autotaxin, as well as extracellular receptors and mediators such as CSF1R, TBXA2R, and WISP1. Conclusions: Ongoing clinical research in IPF reflects a broad diversification of molecular targets; however, translational success remains limited. Current evidence suggests that biological complexity, pathway redundancy, and systemic constraints significantly restrict the clinical impact of single-target strategies. Future progress will likely depend on improved patient stratification, combination approaches, and biomarker-guided trial design rather than isolated pathway modulation. Full article

Background: Perioperative immunotherapy has emerged as a promising strategy for improving outcomes in patients with resectable head and neck squamous cell carcinoma (HNSCC). However, its biological rationale, clinical evidence, and optimal implementation remain incompletely defined. Methods: We conducted a narrative review of the current literature, integrating preclinical and clinical evidence on perioperative immune checkpoint inhibitor (ICI) therapy in resectable HNSCC, with particular attention to the immunological impact of surgery, tumor-draining lymph nodes, and treatment sequencing. Results: Neoadjuvant immunotherapy exploits the presence of intact tumor antigen and preserved lymphatic architecture, enabling broad T-cell priming, clonal expansion, and systemic immune memory formation. In contrast, adjuvant immunotherapy primarily targets residual microscopic disease and relies on preexisting tumor-reactive T cells, suggesting that these strategies are biologically distinct. Early-phase clinical trials have demonstrated the safety and feasibility of perioperative ICIs, with evidence of pathological responses. Recent phase III trials, including KEYNOTE-689 and NIVOPOSTOP, have provided practice-relevant evidence supporting the integration of ICIs into perioperative treatment, demonstrating improved event-free survival and clinical outcomes in selected populations. Several challenges remain, including optimal patient selection, lack of validated biomarkers, and treatment sequencing after perioperative ICI exposure. Conclusions: Perioperative immunotherapy represents a promising practice-relevant strategy in resectable HNSCC. Further studies are required to refine patient selection, develop predictive biomarkers, and optimize treatment sequencing to maximize clinical benefit. Full article

The therapeutic landscape of advanced and recurrent endometrial cancer (EC) has evolved substantially in recent years due to the integration of molecular classification and novel systemic therapies. This review summarizes current treatment strategies in advanced EC, focusing on immunotherapy, targeted therapies, and molecularly guided approaches. Immune checkpoint inhibitors (ICIs) have become a cornerstone of treatment, particularly in mismatch repair-deficient (dMMR)/microsatellite instability-high (MSI-H) tumors, where durable clinical benefit has been observed. Recent phase III trials demonstrated that the addition of ICIs to platinum-based chemotherapy significantly improves progression-free survival in the first-line setting, especially in dMMR disease, with more modest but clinically meaningful benefit in mismatch repair-proficient (pMMR) tumors. In the post-platinum setting, combinations such as pembrolizumab plus lenvatinib have expanded treatment options for pMMR patients, despite increased toxicity. Advances in molecular profiling, including the ProMisE classification, are increasingly guiding treatment personalization. Emerging therapies, including PARP inhibitors and antibody–drug conjugates targeting HER2 and Trop-2, are showing promising activity. Despite these advances, challenges remain regarding resistance mechanisms, optimal treatment sequencing, and predictive biomarkers beyond MMR status. Full article

Background/Objectives: The integration of locoregional and systemic therapies represents a promising strategy in hepatocellular carcinoma (HCC). Yttrium-90 (Y-90) radioembolization provides durable local tumor control, while immune checkpoint inhibitors (ICIs) improve systemic disease outcomes. This review evaluates the biological rationale, clinical evidence, and emerging role of combination Y-90 radioembolization and immunotherapy in HCC. Methods: A semi-systematic (PRISMA-informed) literature review of PubMed/MEDLINE through September 2025 was conducted, including clinical trials, retrospective and prospective studies, and translational investigations evaluating Y-90 radioembolization, immunotherapy, and their combination. Results: Preclinical and translational studies demonstrate that Y-90 radioembolization induces immunogenic cell death, enhances antigen presentation, and activates immune pathways including interferon signaling and STING-mediated responses, supporting a mechanistic basis for potential synergy with ICIs. Early clinical studies, including phase I/II trials, report objective response rates ranging from approximately 30% to 41.5% and median overall survival up to 20.9 months in selected populations. Treatment-related grade ≥ 3 adverse events range from 10% to 25%, comparable to monotherapy approaches. However, outcomes vary across heterogeneous patient populations, and cross-trial comparisons remain limited. Ongoing prospective trials are evaluating combination strategies incorporating contemporary first-line regimens, including atezolizumab plus bevacizumab and the STRIDE regimen. Conclusions: Combination Y-90 radioembolization and immunotherapy demonstrates a strong biological rationale and encouraging early clinical signals, with acceptable safety profiles. However, current evidence remains preliminary and derived from non-randomized studies. Ongoing randomized trials are required to define optimal patient selection, treatment timing, and sequencing, and to establish whether combination therapy provides meaningful benefit over current standards of care. Full article

Background/Objectives: Vaccine clinical trials face high costs, long timelines, and variable progression rates, yet systematic evidence linking trial design features to progression outcomes remains limited. This study aimed to identify trial design features associated with vaccine trial progression and to explore robust design configurations using machine learning approaches. Methods: We analyzed 1618 vaccine trials registered from 2012 to 2022. Progression was defined as phase advancement (phase I/II) or regulatory authorization (phase III). Logistic regression assessed associations with progression. Random forest classifiers with cross-validation were used to estimate predicted progression probabilities based on combinations of design features. Monte Carlo simulations compared model-identified robust configurations with randomly generated configurations. Results: Among 1618 trials, 579 achieved phase progressions, corresponding to an overall observed progression rate of 35.8%. Larger sample size, preventive vaccine purpose, COVID-19 indication, and enrollment across all age groups were consistently associated with higher observed odds of progression in both univariable and multivariable logistic regression analyses. In machine learning analyses, the pooled mean predicted progression probability of model-identified robust configurations was 48.93%, compared with 39.44% for historically observed design configurations, corresponding to a relative increase of 24.1%. Simulations further showed a lower projected cumulative development duration (106.87 vs. 128.25 months; −16.7%) and reduced projected cost (USD 100.67M vs. USD 108.33M; −7.1%) for robust configurations compared with historical strategies. Conclusions: This study provides a data-driven framework for characterizing historical vaccine trial design patterns. By integrating machine learning with observational registry data, it supports hypothesis generation and descriptive benchmarking of design features that may inform the design of future prospective or causal investigations. Full article

Background and Objectives: Relapsed or refractory (R/R) B-cell non-Hodgkin lymphomas (B-NHL) remain associated with poor outcomes despite advances in chemoimmunotherapy and chimeric antigen receptor (CAR) T-cell therapy. Many patients are ineligible for or relapse after cellular therapies, highlighting the need for effective off-the-shelf immunotherapeutic approaches. CD20 × CD3 bispecific antibodies (BsAbs) redirect endogenous T cells against malignant B cells and have emerged as a promising therapeutic class in B-NHL. To summarize current clinical evidence regarding mosunetuzumab, glofitamab, epcoritamab, and odronextamab in B-NHL, focusing on efficacy, safety, and emerging therapeutic applications. Materials and Methods: A structured review of published phase I–III clinical trials evaluating the four currently approved CD20 × CD3 BsAbs in B-NHL was conducted. Efficacy outcomes, durability of response, and safety data were assessed across indolent and aggressive lymphoma subtypes. Results: CD20 × CD3 BsAbs demonstrated substantial and durable clinical activity in heavily pretreated B-NHL, including patients with prior CAR T-cell exposure. Mosunetuzumab showed high response rates and durable remissions in follicular lymphoma (FL), while glofitamab demonstrated significant efficacy in aggressive lymphomas, particularly diffuse large B-cell lymphoma (DLBCL). Epcoritamab exhibited consistent activity across lymphoma subtypes with favorable tolerability supported by subcutaneous administration and step-up dosing. Odronextamab also demonstrated clinically meaningful responses in both FL and DLBCL, including high-risk populations. Across studies, cytokine release syndrome (CRS) was the most common adverse event, predominantly low grade and manageable with established mitigation strategies. Immune effector cell-associated neurotoxicity syndrome (ICANS) was uncommon. Infections and hematologic toxicities, particularly neutropenia, represented clinically relevant adverse events across all treatment programs, highlighting the need for special supportive care. Conclusions: CD20 × CD3 BsAbs represent a major therapeutic advancement in R/R B-NHL, combining high clinical activity, manageable toxicity, and off-the-shelf availability. Their expanding integration into earlier treatment settings and combination strategies is expected to further reshape the therapeutic landscape of B-NHL. Full article

Epithelial ovarian cancer (EOC) remains one of the most lethal gynecologic malignancies, largely owing to advanced-stage presentation, high rates of relapse, and the eventual emergence of therapeutic resistance. Despite the transformative success of immune checkpoint inhibitors (ICIs) across multiple solid tumors, their clinical impact in ovarian cancer has been comparatively modest. This literature review provides a comprehensive synthesis of recent advances in ICI strategies for ovarian cancer (OC), with particular emphasis on phase II and III clinical trials evaluating programmed cell death protein 1 (PD-1), programmed death-ligand 1 (PD-L1), cytotoxic T-lymphocyte–associated protein 4 (CTLA-4), and T cell immunoglobulin and mucin-domain-containing-3 (TIM-3)-directed therapies. Accumulating evidence indicates that PD-1/PD-L1 monotherapy yields limited clinical activity in unselected OC populations, with low objective response rates and minimal survival benefit. Dual checkpoint blockade with PD-1 and CTLA-4 inhibitors demonstrates enhanced antitumor activity, particularly in clear cell ovarian carcinoma (CCOC), albeit at the expense of increased immune-related toxicity. Large randomized trials incorporating ICI into first-line chemotherapy or maintenance settings have largely failed to improve outcomes in biomarker-unselected cohorts. Available evidence demonstrates that combinatorial approaches integrating ICI with anti-angiogenic agents, PARP inhibitors, or neoadjuvant chemotherapy provide modest benefit in selected molecular and histologic subgroups. Early-phase investigations of TIM-3–targeting strategies further expand the immunotherapeutic landscape, although clinical efficacy remains preliminary. Current evidence underscores that OC is not uniformly responsive to immunotherapy and that rational combination strategies, biomarker-driven patient selection, and improved understanding of tumor immune microenvironment heterogeneity are essential to unlocking the full therapeutic potential of ICI in this disease. Full article