GEOapplication/xmlftp://ftp.ncbi.nlm.nih.gov/geo/series/GSE322nnn/GSE322775/primaryOK200TranscriptomicsMus musculusExpression profiling by high throughput sequencinghttps://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE322775GEOGSEfalseCoordinated immune activation following KRAS inhibition reveals molecular pathways that potentiate and limit anti-tumor immunityWhile mutant-specific KRAS inhibitors are approved to treat cancer, a deeper understanding of intratumoral changes driven specifically by KRAS inhibition is needed to maximize therapeutic responses. 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. Combination treatment of KRAS(G12C)i with anti-PD-1 overcomes immune activation barriers by prolonging the activation window and clonal persistence for T cells and by promoting the re-wiring of pro-inflammatory macrophages associated with higher survival, Furthermore, combination treatment amplifies intercellular communication among non-PD-1+ expressing cells to perpetuate dendritic cell activation. Our findings connect neoplastic KRAS inhibition with the coordination of distinct levers for immune activation and reveal pro- and anti-tumor mechanisms that can be modulated following specific treatment types to contain malignant growth.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 musculus