Tumor Immune Microenvironment and Checkpoint Inhibition in Clear Cell Ovarian Carcinoma: Bridging Tumor Biology and Clinical Application in Immunotherapy.

Abstract

Clear cell ovarian carcinoma is a rare and aggressive histologic subtype of epithelial ovarian cancer, characterized by a chemoresistant phenotype and distinct immunogenomic features. Despite early-phase trials showing a limited response to immune checkpoint inhibitors (ICIs), emerging evidence reveals a biologically diverse tumor immune microenvironment, with implications for the efficacy of immunotherapies. Preclinical studies highlight paradoxical associations between immune infiltration and prognosis, as well as genomic drivers-including KRAS, MYC, PI3KCA, TP53, PTEN, and ARID1A-that shape immune evasion and checkpoint ligand expression. Clinically, ICI monotherapy yields modest benefit, while combination regimens-particularly dual checkpoint blockade and targeted co-inhibition-offer improved outcomes. Biomarkers such as PD-L1 CPS ≥ 1%, ARID1A mutations, elevated tumor mutational burden, and PIK3CA alterations emerge as promising predictors of therapeutic response. This review integrates current preclinical and clinical data to propose a precision immunotherapy framework tailored to the immunogenomic landscape of clear cell ovarian carcinoma.