PIK3CA mutation-induced immune microenvironment remodeling sensitizes cervical cancer to immunotherapy

Abstract

PIK3CA is one of the most frequently mutated genes in cervical cancer (CC). However, its clinical utility is hampered by paradoxical treatment-dependent outcomes, restricting its application in precision oncology. To address this issue, we constructed a high-resolution single-cell transcriptomic atlas of the CC tumor microenvironment. It was found that PIK3CA mutations induce a dichotomous TME, simultaneously associated with marked T-cell inflammation and resistance to adaptive immune responses. Malignant epithelial subsets induce CD8⁺ T-cell exhaustion through both canonical PD-L1-PD-1 signaling and the non-canonical SPP1-CD44 axis. Additionally, PIK3CA mutations enrich for MMP9⁺ macrophages that promote tumor angiogenesis through ANGPTL4 signaling. This dual landscape of T-cell exhaustion and active angiogenesis provides a framework for the observed synergy between PD-1 blockade and anti-angiogenic therapies. The findings demonstrate that the presence of PIK3CA mutations is a key predictive biomarker for guiding combination immunotherapy in CC and identify a rational basis for co-targeting distinct immune and vascular resistance pathways.

Keywords: PIK3CA mutation; cervical cancer; immunotherapy; single-cell RNA sequencing; tumor microenvironment.