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IBI351, a novel KRASG12C inhibitor, enhances αPD-1 efficacy in KRASG12C mutant lung cancer

ABSTRACT: The clinical benefit of immune checkpoint inhibitor (ICI) treatments in patients with advanced KRAS mutant non-small-cell lung cancer (NSCLC) is limited. Here, we found IBI351, a selective KRASG12C inhibitor, significantly enhanced the efficacy of anti-PD-1 antibody (αPD-1) in inhibiting tumor growth in vitro and in vivo. Mechanistically, IBI351 inhibited STAT3 activity, leading to downregulation of stanniocalcin 1 (STC1). STC1 anchors calreticulin (CRT) to the mitochondrial membrane; its downregulation promoted CRT translocation to the cancer cell surface, increasing the ‘eat me’ signal and enhancing T cell infiltration. In clinical specimens from KRASG12C mutant NSCLC patients treated with PD-1 inhibitors, low STC1 expression correlated with better treatment response and prolonged survival. Together, these findings demonstrate that IBI351 enhances ICI efficacy by suppressing the STAT3-STC1 axis and promoting CRT-mediated phagocytosis, supporting further clinical evaluation of this combination.

ORGANISM(S): Homo sapiens

PROVIDER: GSE328294 | GEO | 2026/06/05

REPOSITORIES: GEO

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Project description:Background: The tumor cell-intrinsic function of programmed cell death-ligand 1 (PD-L1) is poorly understood. The roles of the intrinsic function of PD-L1 in interleukin (IL)-6-mediated immunosuppression and the response to immune checkpoint inhibitors (ICIs) in non-small cell lung cancer (NSCLC) were investigated. Methods: Cohorts of NSCLC patients treated with ICI and public datasets were analyzed. PD-L1-overexpressing and PD-L1-knockdown NSCLC cells were submitted to RNA-seq, in vitro analyses, ChIP-qPCR, CUT&Tag, and biochemical assays. Human myeloid-derived suppressor cells (MDSCs) sorted from peripheral blood mononuclear cells were co-cultured with NSCLC cells, and then assessed for their immunosuppressive activity on T-cells. Mouse Lewis lung carcinoma (LLC) cells with PD-L1 overexpression/or knockdown were subcutaneously injected into wild-type or PD-1-knockout C57BL/6 mice in the presence of IL-6 and/or PD-1 blockade. Results: In the ICI cohort with RNA-seq data, the IL-6/Jak/Stat3 pathway was enriched and IL-6 expression was higher in patients with no response to ICI in PD-L1-high NSCLCs. IL-6 expression in PD-L1-high NSCLCs correlated positively with MDSCs and Tregs, but negatively with cytotoxic lymphocytes. In another ICI cohort, a higher baseline serum IL-6 level was associated with poor clinical outcome after ICI therapy. PD-L1 activated Jak2/Stat3 signaling by binding to and inhibiting tyrosine phosphatase PTP1B. PD-L1 also bound to p-Stat3 in the nucleus, thus promoting the activity of p-Stat3 on the transcription of several cytokines (IL-6, TGFβ, TNFα, IL-1β) and chemokines (CXCL1, CXCL3, CXCL8). PD-L1-overexpressing NSCLC cells enhanced the migration and immunosuppressive activity of human MDSC in vitro, mediated by IL-6 and CXCL1. In both wild-type and PD-1-knockout mice, PD-L1-overexpressing mouse lung tumors were heavily infiltrated by MDSCs with high immunosuppressive function. Treg numbers were increased while the numbers of granzyme B+ or IFNγ+ CD8 T-cells decreased. These responses were shown to be mediated by IL-6 secreted from PD-L1-overexpressing tumor cells. Combined blockade of PD-1 and IL-6 was effective in tumor control and decreased MDSCs while increasing granzyme B+ or IFNγ+ CD8 T-cells. Conclusions: The tumor-cell-intrinsic function of PD-L1 contributes to immunosuppression and tumor progression by MDSCs through the IL-6/Jak/Stat3 pathway, which may serve as therapeutic target to improve ICI efficacy in patients with PD-L1-high NSCLC.

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IBI351, a novel KRASG12C inhibitor, enhances αPD-1 efficacy in KRASG12C mutant lung cancer

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