Coordinated immune activation following KRAS inhibition reveals molecular pathways that potentiate and limit anti-tumor immunity

Here we apply single-cell RNA-seq, flow cytometry, and spatial transcriptomics to distinguish mechanisms of tumor control after KRASG12C inhibition (KRAS(G12C)i), MEK inhibition (MEKi) and following combination therapy with KRAS(G12C)i and PD-1 blockade.

Despite inhibiting overlapping pathways, KRAS(G12C)i drives the adaptation of distinct neoplastic cell fates affecting metabolism and cell cycle regulation, leading to synergistic tumor suppression after co-administration with MEKi. In turn, this modulates intercellular communication patterns and induces robust dendritic cell maturation and PD-1+ macrophage activation mediated through non-immune mediators. Both KRAS(G12C)i and MEKi elicit a similar magnitude of cytotoxic T-cell infiltration despite a reduced capacity for T-cell proliferation after MEKi, implicating distinct adaptive immune activation mechanisms.