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Targeting XIAP-coordinated PKC signaling resensitizes PD-1-refractory tumors for rechallenge
Jupeng Yuan1,2, Yujiao Ma1,2, Ying Dong1,2
1Department of Shandong Provincial Key Laboratory of Precision Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong 250000, People's Republic of China.
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.
Insights
Protein kinase C (PKC) activity predicts non-small cell lung cancer outcomes. Inhibiting PKC overcomes resistance to PD-1 blockade by promoting cell death and T cell responses, offering a new strategy for refractory cancers.
Area of Science:
- Oncology
- Immunology
- Molecular Biology
Background:
- Immune-checkpoint blockade (ICB) targeting PD-1/PD-L1 has transformed cancer therapy.
- Primary and acquired resistance limit ICB efficacy, necessitating alternative strategies.
- The mechanisms underlying ICB resistance and effective rechallenge remain unclear.
Purpose of the Study:
- To identify biomarkers and therapeutic targets for overcoming anti-PD-1 resistance in non-small cell lung cancer (NSCLC).
- To elucidate the molecular mechanisms by which protein kinase C (PKC) inhibition impacts anti-PD-1 refractory tumors.
- To evaluate PKC inhibition as a salvage strategy in combination with other immunotherapies.
Main Methods:
- Assessed substrate-based PKC activity as a prognostic biomarker in NSCLC.
- Investigated the effects of pan-PKC inhibition on anti-PD-1-refractory tumor models.
- Analyzed downstream signaling pathways including Caspase-3/GSDME, GSK3β, PD-L1 degradation, CCL4-CCR5, XIAP, PTEN, and Wnt/β-Catenin-ATF3.
- Evaluated combination therapies with anti-CTLA-4 and anti-PD-1/PD-L1 in resistant models.
Main Results:
- PKC activity serves as a prognostic biomarker in NSCLC.
- Pan-PKC inhibition overcomes anti-PD-1 resistance by inducing immunogenic pyroptotic cell death.
- PKC inhibition promotes tumor-intrinsic PD-L1 degradation and enhances CD8+ T cell recruitment and function via CCL4-CCR5 signaling.
- PKC blockade destabilizes XIAP, stabilizes PTEN, and suppresses Wnt/β-Catenin-ATF3 signaling, driving CCL4 expression.
- PKC inhibition synergizes better with anti-CTLA-4 than anti-PD-1/PD-L1 in resistant models, reducing regulatory T cells and enhancing CD8+ T cell function.
Conclusions:
- The PKC-XIAP axis is a critical regulator of immune resistance in cancer.
- PKC inhibition represents a promising therapeutic target to overcome ICB resistance.
- Combined PKC inhibition and anti-CTLA-4 therapy offers a potential salvage strategy for ICB-refractory cancers.
