Targeting neoantigens conserved across organs and species overcomes tumor immune escape

Neoantigen-targeted immunotherapies hold promise for cancer treatment, but current personalized approaches are time-consuming and costly. Here, we identify neoantigens encoded by Ptprs and Igf2r that are shared across murine mismatch repair-deficient colorectal and breast tumors and unexpectedly conserved in human colorectal, endometrial, gastric, and prostate cancers. These neoantigens elicit spontaneous, organ-spanning CD8+ T cell-mediated memory responses that are enhanced by immune checkpoint blockade. Vaccination with mRNA/lipid nanoparticles encoding these conserved neoantigens suppresses tumor growth across prophylactic and therapeutic models, including checkpoint-resistant orthotopic tumors. Tumor rejection is accompanied by antigen spreading, abscopal effects, and infiltration by clonally diverse T cells, dendritic cells, and MHC I/II+ macrophages producing CXCL9/10, CCL5/8, and TNF. Tumor cells also show activation of innate and adaptive pathways, including MHC and ISGs overexpression. Our results uncover a conserved anti-tumor immune mechanism and support the development of off-the-shelf neoantigen vaccines across tissues and species.