{"database":"GEO","file_versions":[{"headers":{"Content-Type":["application/json"]},"body":{"files":{"Other":["ftp://ftp.ncbi.nlm.nih.gov/geo/series/GSE322nnn/GSE322775/"]},"type":"primary"},"statusCode":"OK","statusCodeValue":200}],"scores":null,"additional":{"omics_type":["Transcriptomics"],"species":["Mus musculus"],"gds_type":["Expression profiling by high throughput sequencing"],"full_dataset_link":["https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE322775"],"repository":["GEO"],"entry_type":["GSE"],"additional_accession":[]},"is_claimable":false,"name":"Coordinated immune activation following KRAS inhibition reveals molecular pathways that potentiate and limit anti-tumor immunity","description":"While 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.","dates":{"publication":"2026/06/27"},"accession":"GSE322775","cross_references":{"GSM":["GSM9558221","GSM9558188","GSM9558220","GSM9558201","GSM9558223","GSM9558222","GSM9558200","GSM9558189","GSM9558225","GSM9558203","GSM9558224","GSM9558202","GSM9558227","GSM9558205","GSM9558204","GSM9558226","GSM9558207","GSM9558229","GSM9558228","GSM9558206","GSM9558209","GSM9558208","GSM9558191","GSM9558190","GSM9558193","GSM9558192","GSM9558195","GSM9558194","GSM9558230","GSM9558197","GSM9558196","GSM9558210","GSM9558199","GSM9558232","GSM9558198","GSM9558231","GSM9558234","GSM9558212","GSM9558233","GSM9558211","GSM9558214","GSM9558213","GSM9558216","GSM9558215","GSM9558218","GSM9558217","GSM9558219"],"GPL":["34328"],"GSE":["322775"],"taxon":["Mus musculus"]}}