Fig. 7

Targeting RIPK1 increases the sensitivity of lung tumors to anti-PD-1 therapy. (A) Kaplan-Meier curves predicting survival of LUSC patients receiving anti-PD-1 therapy based on net changes in TRIM28 mRNA levels in the LUSC-GSE93157-anti-PD-1 datasets. (B) Kaplan-Meier curves predicting survival of melanoma patients receiving anti-PD-1 therapy based on net changes in TRIM28 mRNA levels in the melanoma-GSE91061-anti-PD-1 datasets. (C-D) C57BL/6J mice were subcutaneously injected with CMT-167 cells and treated with anti-PD-1, PK68 (RIPK1 inhibitor), PK68 plus anti-PD-1, or isotype control and vehicle. Tumor growth was monitored until the experimental endpoints. Data are shown as mean ± SEM. Tumor growth curves were shown. (E-F) Representative images of IHC for CD8, Gr-1, and S100A8 + S100A9 in indicated mouse tumors (E) and IHC quantification (F). The scale bars represent 50 μm. Error bars indicate mean ± SEM. Statistics calculated using one-way ANOVA post hoc Tukey test for multi-group or two-tailed Student’s t-test for two-group comparisons. **p < 0.01. (G) High TRIM28 expression is positively correlated with MDSCs infiltration in multiple cohorts of cancer patients. TRIM28 promotes NF-κB activation by regulating K63-linked ubiquitination of RIPK1, leading to increased expression of the cytokine CXCL1, a chemoattractant for MDSCs via the CXCL1-CXCR2 axis. TRIM28-recruited MDSCs antagonize effector CD8⁺T cells in the tumor immune microenvironment of NSCLC, promoting anti-PD-1 resistance