PIK3CA mutant cervical cancer is selectively suppressed by PI3Kα inhibition (Alpelisib/BYL-719 and Inavolisib/GDC-0077) and cooperates with HPV directed T cell therapy.

Cervical cancer is largely driven by human papillomavirus (HPV) infection, yet clinically actionable molecular subtypes and effective targeted therapies remain limited. Here, we define biologically and clinically relevant subtypes and evaluate targeted therapeutic strategies. Analysis of public datasets, coupled with functional studies in cervical cancer cell lines and immune assays, identified three subtypes: (I) PIK3CA wild-type without YAP1 amplification, (II) PIK3CA-mutant without YAP1 amplification, and (III) PIK3CA wild-type with YAP1 amplification. Notably, YAP1 amplification is associated with poorer patient survival. The PI3Kα-specific inhibitors, Alpelisib (BYL-719) and Inavolisib (GDC-0077), selectively inhibited proliferation in multiple PIK3CA-mutant cervical cancer cell lines but had minimal effect in PIK3CA wild-type cells. Alpelisib further reduced expression of HPV16 E7, PD-L1 (CD274), YAP1, and EGFR specifically in PI3Kα-mutant models. In an HPV16-positive, HLA-A2-positive, PIK3CA-mutant cell line (CaSki), antigen-specific donor T cells (NexImmune) induced cytotoxicity in a dose-dependent manner. Importantly, combining BYL-719 with T-cell therapy enhanced tumor cell killing, with maximal effects observed following drug pretreatment prior to T-cell exposure. These findings identify actionable molecular subtypes of cervical cancer and support targeting PI3Kα in PIK3CA-mutant tumors. Moreover, combining PI3K inhibition with antigen-specific immunotherapy represents a promising strategy to improve outcomes in advanced HPV16-associated cervical cancer.