Targeting XIAP-coordinated PKC signaling resensitizes PD-1-refractory tumors for rechallenge.

Despite revolutionizing oncology, PD-1/PD-L1-directed immune-checkpoint blockade (ICB) is limited by primary or acquired resistance that is routinely countered-without mechanistic clarity-by empiric rechallenge. Here, we identify substrate-based protein kinase C (PKC) activity as a prognostic biomarker in non-small cell lung cancer and a therapeutic target in anti-PD-1-refractory tumors. Pan-PKC inhibition overcomes anti-PD-1 resistance by inducing Caspase-3/GSDME-dependent immunogenic pyroptotic cell death, promoting tumor-intrinsic PD-L1 degradation via GSK3β activation, and enhancing CD8+ T cell recruitment and effector function through tumor-derived CCL4-CCR5 signaling. Mechanistically, PKC blockade destabilizes XIAP, relieving caspase inhibition, stabilizing PTEN, and suppressing Wnt/β-Catenin-ATF3 signaling to drive CCL4 expression. In resistant models, PKC inhibition synergizes more effectively with anti-CTLA-4 than with anti-PD-1/PD-L1, in association with reduced intratumoral regulatory T cells and reinforcement of CD8+ T cell effector function. These findings define the PKC-XIAP axis as a central regulator of immune resistance and provide a mechanistic rationale for PKC inhibition plus anti-CTLA-4 as a salvage strategy in ICB-refractory cancers.