Background Acquired resistance to KRAS G12C inhibitor sotorasib remains a critical challenge in non-small cell lung cancer treatment. A deeper, rational understanding of resistance mechanisms can enable the development of therapeutic strategies to overcome resistance. Methods We established a syngeneic resistant model after prolonged AMG-510 treatment in C57BL/6 mice. In addition, the in vitro co-culture model and multiple methods including flow cytometry and western blot were used to assess the changes of immune microenvironment during resistance. Finally, a serial combinatorial therapy strategy was applied in the resistant mouse model to evaluate its ability to reverse resistance. Results Upregulation of PD-L1 in KRAS G12C tumors drives an immunosuppressive tumor microenvironment and promotes acquired resistance characterized by reduced infiltration of cytotoxic CD8 + T cells and a marked expansion of myeloid-derived suppressor cells through JAK2/STAT3/IL-6 Pathway. These mechanisms promote tumor immune evasion and protection from cell apoptosis, thereby establishing a microenvironment that sustains acquired resistance to sotorasib. Critically, sequential administration of a PD-L1 inhibitor (PD-L1i) effectively reprogrammed the immunosuppressive microenvironment, restoring antitumor immunity and re-sensitizing resistant tumors to sotorasib treatment. Conclusions These results identify the PD-L1-driven immunosuppressive microenvironment as a key mediator of sotorasib resistance and propose PD-L1i as a synergistic strategy to overcome resistance, which warrants clinical exploration of sequential or combinatorial regimens.
Liu et al. (2026) studied this question.