Combined KRAS inhibition and immune therapy generates durable complete responses in an autochthonous PDAC model

Abstract Pancreatic ductal adenocarcinoma (PDAC) resists conventional chemo/radiation and immunotherapy. In PDAC, oncogenic KRAS (KRAS*) drives glycolysis in cancer cells to consume available glucose and produce abundant lactate, creating profound immune suppression in the tumor microenvironment. Here, we combined KRAS* inhibition with agents targeting the major arms of the immunity cycle: CXCR1/2 inhibitor for myeloid cells, antagonistic anti-LAG3 antibody for T cells, and agonistic anti-41BB antibody for dendritic cells. This combination elicited robust anti-tumor regression in iKPC mice bearing large autochthonous tumors. While untreated mice succumbed within 3 weeks, sustained treatment led to durable complete tumor regression and prolonged survival in 36% of mice at 6 months. Mechanistic analyses revealed enhanced T cell infiltration and activation, depletion of immunosuppressive myeloid cells, and increased antigen cross-presentation by dendritic cells within the tumor core. These findings highlight the promise of KRAS* inhibitors alongside immunotherapy as a potential PDAC treatment avenue, warranting clinical investigation.