Current Trends and Future Prospects in the Use of Immunotherapy in Ovarian Cancer-Editorial

NIKOLAOS GAVALAS^*

• National and Kapodistrian University of Athens, Athens, Greece

Ovarian cancer is the most prevalent form of cause of gynecologic cancer in terms of mortality due to a number of factors i.e. late-stage diagnosis, frequent relapse, and resistance to current treatment regimes such as chemotherapy. Standard treatments including surgical cytoreduc on and pla num-based chemotherapy, tend to yield high ini al response rates; however, most advanced-stage pa ents experience disease recurrences, highligh ng the urgent need for alterna ve therapies. In addi on to other therapeu c modali es, immunotherapy has drawn a en on as an innova ve approach with the promising poten al of improved outcomes by leveraging the immune system's natural ability to recognize and a ack tumor cells.In recent years, relevant publica ons regarding ovarian cancer immunotherapy have been steadily increasing. At the same me, bibliometric analyses confirm rapid expansion of this research field since 2019, as the discipline transi ons from founda onal trials toward precision medicine and combina on strategies. Key obstacles to immunotherapy's efficacy in ovarian cancer include tumor heterogeneity combined with an immunosuppressive microenvironment. Ovarian tumors, in most cases, are infiltrated by immune cells, including CD3+ and CD8+ T cells and macrophages. These popula ons are o en func onally suppressed or reprogrammed by the tumor. Also, the upregula on of immune checkpoint molecules such as PD-1 and PD-L1, along with TGF-β and CTLA-4, impedes cytotoxic lymphocyte ac vity, enabling tumor evasion from immune surveillance (1).Several papers employ cu ng-edge methods like single-cell sequencing to profile the ovarian tumor immune microenvironment in detail (2). This approach sheds light to tumor cell subpopula ons, immune cell phenotypes, and gene expression signatures that dictate immunologic dysfunc on and therapy resistance. In this collec on, Zhao et al (3) report that succinic acid can reshape immune cell infiltra on and func on, targe ng hub genes SPP1, SLPI, and CD9, poten ally disrup ng tumor defenses. Immunotherapeu c strategies for ovarian cancer currently encompass targets such as checkpoint inhibitors e.g. PD-1/PD-L1 antagonists, cell-based approaches like CAR-T and adop ve T cell transfer, and monoclonal an bodies. While immune checkpoint inhibitors have revolu onized treatment for other malignancies, their clinical value in ovarian cancer is tempered by low tumor muta onal burden and limited immunogenicity, hence termed a "cold tumor" (4). Objec ve response rates remain modest, though subsets of pa ents with high PD-L1 expression may benefit more consistently (5). S ll, PD-L1 status is not a fully reliable predictor, as both PD-L1-posi ve and PD-L1-nega ve pa ents may respond to therapy, underscoring the complexity of the immune landscape.Recent literature explores alterna ve checkpoints (such as TIGIT, CD155, and DNAM-1) in combina on therapies, aiming to enhance cytotoxic T cell and natural killer cell ac vity, increase tumor an gen presenta on, and overcome suppression within the tumor microenvironment (1). Wang et.al (6), in this collec on, along other published literature refers to mul modal approaches, including checkpoint inhibitors, targeted agents (e.g., PARP inhibitors), and an angiogenic drugs (bevacizumab), that are under inves ga on to extend immunotherapeu c benefits. Chemotherapy resistance stemming from pla num compound treatments, remains a profound clinical challenge (7). Resistance mechanisms include altered cell death pathways, such as autophagy and immunosuppression orchestrated by COX-2 and tumorassociated macrophages (TAMs). Promising results have been generated by targe ng the above, as TAM reac vity modula on for example may restore an tumor immunity and improve treatment outcomes, with a possible significant impact on pa ents with pla num-resistant disease. The discovery of robust predic ve biomarkers is pivotal to op mizing immunotherapy.Several studies focus on signatures of immune infiltra on, tumor muta on burden, and molecular markers as tools for stra fying pa ents and customizing therapies. In previous papers (8) but also in this collec on, Gronauer et.al ( 9), perform single-cell RNA sequencing allowing for deep profiling of tumor heterogeneity, revealing popula onspecific tumor vulnerabili es and new therapeu c targets, highligh ng the necessity for precision medicine applica ons in this disease. Recent clinical trials validate targeted immunotherapy approaches but underscore variable efficacy. While the administra on of pembrolizumab, which is an an -PD-1 agent demonstrates ac vity in some high PD-L1-expressing pa ents, overall survival improvements remain limited for the general affected popula on. The presence of adverse events, including immune-related toxici es and autoimmune responses, should impose diligent risk management to preserve the quality of life of pa ents.Targeted sequencing (10) and drug treatment combina ons (1)-immune checkpoint inhibitors plus chemotherapy, targeted drugs, or alterna ve checkpoint blockadesrepresent major foci of contemporary research, aiming to refine therapeu c windows and provide new ones, maximize efficacy, and reduce toxicity. Research trends in ovarian cancer show that research priori es have shi ed from ini al trials and monoclonal an body development to topics such as CAR-T cell therapy, and tumor microenvironment modula on. Influen al research propels the field, guided by emerging insights from genomic databases and landmark trials focused on neoadjuvant and combina on strategies (11).Challenges for the future include treatment-induced toxicity, and slow clinical transla on of gene c discoveries in order to improve survival rates. This editorial aims to highlight the seven papers of this collec on that a empt to contribute to a rapidly maturing field commi ed to overcoming immunotherapy's limita ons in ovarian cancer. Further pathways to advance research include: Mul dimensional tumor profiling via single-cell technologies and advanced bioinforma cs, thus enabling tailored immunotherapeu c interven ons. Con nued explora on of combina on therapies targe ng immune checkpoints, with an emphasis on restoring immune cell func on in resistant, immunosuppressing tumors. Enhanced biomarker iden fica on and characteriza on, either as single molecules or combina ons (signatures) that facilitate stra fied clinical trial designs and personalized treatment algorithms.Further coordinated efforts integra ng basic science, transla onal research, and clinical exper se will accelerate innova on and broaden therapeu c accessibility.