Checkpoint Inhibitor Therapy in Gynecologic Clear Cell Carcinoma: A Narrative Review

Abstract

Background: Gynecologic clear cell carcinoma (CCC) represents a rare and biologically distinct subgroup of gynecologic malignancies arising predominantly from the ovary and endometrium, and less commonly from the cervix and vulva. Characterized by chemoresistance, a high rate of early recurrence, and a paucity of effective second-line therapies, CCC carries a disproportionately poor prognosis compared with other histologic subtypes. The emergence of immune checkpoint inhibitors (ICIs), particularly agents targeting the programmed death-1 (PD-1), programmed death-ligand 1 (PD-L1) axis, and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), has transformed the treatment landscape of multiple solid tumors. However, the immunologic microenvironment of CCC is uniquely complex, characterized by variable PD-L1 expression, moderate tumor mutational burden, a prominent inflammatory infiltrate, and a paradoxically immune-evasive phenotype driven by ARID1A co-mutation and HNF-1 β overexpression. This narrative review synthesizes the available clinical and translational evidence on the efficacy, biomarker landscape, and future directions of ICI therapy in gynecologic CCC. Methods: A comprehensive search of PubMed/MEDLINE, EMBASE, and the Cochrane Library was performed from January 2010 to January 2026, focusing on clinical trials, retrospective studies, and translational analyses reporting outcomes of ICIs in patients with CCC of gynecologic origin. Results: Emerging data from basket trials and histology-specific cohorts suggest modest but potentially clinically meaningful activity of ICIs in CCC, particularly in the recurrent setting and in tumors which harbor mismatch repair deficiency mutations or high tumor mutational burden. Conclusion: Combination strategies incorporating ICIs with VEGF inhibition, PARP inhibition, or targeted agents represent a rational and promising avenue. Standardization of biomarker testing and inclusion of CCC-specific cohorts in future trials are essential to advancing the field.