XIAP-coordinated PKC signaling overcomes immunotherapy resistance via immunogenic rewiring to empower therapeutic rechallenge [RNA-Seq]

By profiling substrate-based protein kinase C (PKC) activity, rather than pan-PKC expression, we uncover a superior biomarker predicting survival and anti-PD-1 responsiveness in non-small cell lung cancer (NSCLC). Critically, pharmacological pan-PKC inhibition overcomes anti-PD-1 resistance across diverse preclinical models through a coordinated immunologic program.

Specifically, PKC blockade triggers Caspase-3/GSDME-dependent immunogenic cell death (ICD) with ATP/HMGB1 release. It concurrently reprograms the tumor microenvironment (TME) by enriching CD8+ T cells and regulatory T cells (Tregs) in a CCR5-dependent manner, while inducing tumor-intrinsic PD-L1 degradation to sustain CD8+ T cell function. Mechanistically, targeting PKC destabilizes XIAP, whose degradation not only unleashes caspase-mediated ICD and PD-L1 degradation but also licenses CCL4 secretion for CCR5-centric TME rewiring.