Immune checkpoint inhibitors in platinum-resistant ovarian cancer: Clinical disappointments, biological lessons, and the reopening of therapeutic opportunities.

Abstract

Immune checkpoint inhibitors (ICIs) have transformed the treatment landscape of several malignancies; however, their efficacy in platinum-resistant ovarian cancer (PROC) remains limited. The immunosuppressive tumor microenvironment (TME) in ovarian cancer constitutes a major barrier to effective antitumor immunity, prompting the development of various strategies to enhance responsiveness to ICIs. This narrative review examines current therapeutic approaches targeting the TME to overcome resistance to ICIs in PROC, with a focus on angiogenesis, innate immunity, and adaptive immune pathways. Despite a strong biological rationale, most chemotherapy-free ICI-based combinations targeting specific immune or stromal components have shown limited and inconsistent clinical benefit. The most notable clinical activity has been observed when ICIs are combined with chemotherapy, particularly in regimens that include anti-angiogenic agents. Recent positive results from a single phase 3 trial evaluating pembrolizumab in combination with weekly paclitaxel, with or without bevacizumab, mark a notable deviation from the predominantly negative outcomes of earlier studies. Nevertheless, it remains uncertain whether this result represents a true paradigm shift or a context-specific effect. Currently, no validated predictive biomarkers exist to reliably identify patients most likely to benefit from ICI-based strategies. The discrepancy between the isolated success of chemo-immunotherapy combinations and the failure of most previous trials highlights the need for further investigation into TME biology. A more comprehensive understanding of TME dynamics and the development of biomarker-driven patient selection strategies will be essential to define the role of ICIs in this challenging clinical context.