Targeting XIAP-coordinated PKC signaling resensitizes PD-1-refractory tumors for rechallenge
Abstract
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.
Article Details
Journal Info
Proceedings of the National Academy of Sciences
National Academy of Sciences
Authors (16)
Jupeng Yuan
Department of Shandong Provincial Key Laboratory of Precision Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan
Yujiao Ma
State Key Laboratory of Green Pesticide, Engineering Research Center of Photoenergy Utilization for Pollution Control and Carbon Reduction, Ministry of Education, College of Chemistry, Central China Normal University (CCNU), 152 Luoyu Road, Wuhan, Hubei 430079, P. R. China
Ying Dong
State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Design and Optimization, and Department of Chemistry
Zengfu Zhang
Department of Shandong Provincial Key Laboratory of Precision Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan
Yuequn Ma
Department of Shandong Provincial Key Laboratory of Precision Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan
Fei Wang
Baoqing Tian
Department of Shandong Provincial Key Laboratory of Precision Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan
Ying Xu
Xiaoliang Wang
Department of Chemistry
Xu Liu
Hanghang Yuan
Department of Shandong Provincial Key Laboratory of Precision Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan
Mei Liu
Zhengyu Wang
School of Clinical Medicine, Shandong Second Medical University
Meng Wu
Jinming Yu
Department of Shandong Provincial Key Laboratory of Precision Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan
Dawei Chen
State Key Laboratory of Chemo and Biosensing, College of Chemistry and Chemical Engineering, Advanced Catalytic Engineering Research Center of the Ministry of Education