Abstract
Colorectal cancer (CRC) exhibits limited responsiveness to immune checkpoint inhibitors (ICIs), largely due to its immunosuppressive tumor microenvironment (TME) and poor baseline immunogenicity. Here, we report that Pseudomonas aeruginosa (P. aeruginosa) triggers caspase-3-dependent pyroptosis in murine CRC MC38 cells, characterized by GSDME cleavage, intracellular reactive oxygen species (ROS) accumulation, and the release of damage-associated molecular patterns (DAMPs). This form of immunogenic cell death promotes robust inflammatory cytokine secretion, upregulation of PD-L1 on tumor cells, and functional maturation of bone marrow-derived dendritic cells (BMDCs) in vitro. In vivo, intratumoral injection of P. aeruginosa leads to significant reprogramming of the TME, including increased expression of proinflammatory genes, DC maturation, and enhanced infiltration of CD8+ T lymphocytes. Notably, combination therapy with P. aeruginosa and an anti-PD-L1 antibody results in synergistic tumor regression, markedly outperforming either monotherapy, without inducing detectable systemic toxicity. Together, our findings reveal that P. aeruginosa-induced pyroptosis serves as a potent immunogenic stimulus that reshapes the CRC tumor microenvironment and overcomes resistance to immune checkpoint blockade. This strategy represents a promising approach to enhance immunotherapy efficacy in poorly immunogenic solid tumors.