Authors
Mohammed L Ibrahim, Dana Foresman, Hong Zheng, Xiaoxian Liu, Mengyu Xie, Theresa A Boyle, Joseph O Johnson, Paulo C Rodriguez, Daniel Abate-Daga, Brian Ruffell, Alexander R Anderson, Eric B Haura, Xiaoqing Yu, Amer A Beg
Published in
Cancer immunology research. Sep 11, 2026. Epub Sep 11, 2026.
Abstract
Inhibition of KRASG12C (G12Ci) has shown promising clinical activity in several cancers; however, emergence of resistance is a major limitation to long-term benefit. It remains unknown how G12Ci impacts the tumor immune microenvironment and its association with resistance. We investigated the immune modulatory impact of the G12Ci sotorasib in KrasG12C/Trp53-/- (KP) lung and colon carcinoma models. Single-cell RNA sequencing of tumors in both models demonstrated sotorasib-induced loss of proliferative tumor cells and to the enrichment of immune-active tumor cells with elevated NF-B and interferon signaling, and elevated MHC-I expression. These changes led to an increased proportion of effector T cells and MHC-IIhi macrophages in the tumors, and a reduced proportion of regulatory myeloid cells. Furthermore, sotorasib-resistant tumors exhibited a marked reduction of MHC-Ihigh immune-active tumor cells and immune cell type changes. Enrichment of immune-active tumor cells was associated directly with sotorasib-induced activation of NF-B and STAT1, leading to heightened responsiveness to inflammatory cytokines and to upregulation of MHC-I and chemokine expression. These findings indicate that modulation of immune-active tumor cell populations is a key mechanism associated with G12Ci therapeutic efficacy and the development of resistance.
PMID:
42726935
Bibliographic data and abstract were imported from PubMed on 12 Sep 2026.
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