Hypermutation induced by inactivation of mismatch repair (MMR) leads to increased neoantigen formation and immune surveillance in colorectal cancer (CRC) and in several other malignancies. Interestingly, commonly used cytotoxic agents present a known mutagenic potential, and exposure to chemotherapy has been associated to an increased tolerance to DNA damage. We investigated the impact of rationally designed combinations of chemotherapeutics on the generation of hypermutation and immunogenicity in otherwise immune refractory MMR-proficient CRC. We found that combinatorial treatment with cisplatin (CDDP) and temozolomide (TMZ) induces clonal and subclonal hypermutability resulting in an increase in predicted neoantigens. This combination specifically alters the immune fitness of the tumors and ultimately leads to immunoediting of chemotherapy-induced neoantigens and CD8+ T cellmediated tumor rejections. Treatment-induced hypermutation and immune surveillance were also confirmed in a model of immune-refractory breast cancer. By following the fate of treatment-induced mutations in the CRC model, we discovered that the neoantigens undergoing active immune deletion derive from mutations that are etiologically linked to chemotherapy treatment. Importantly, mice that had successfully rejected cells treated with CDDP-TMZ are vaccinated against their untreated counterpart. The same effect is not observed when priming is performed using the clinically approved combination of 5-flourouracil, oxaliplatin and irinotecan (FOLFOXIRI). Treatment with CDDP, TMZ, and anti-PD1 induces long lasting responses and complete rejections. Altogether, these results indicate that rational combinations of chemotherapeutic agents can promote immune surveillance through the induction of immunologically-relevant mutations.