Hu et al. demonstrated that Pseudomonas aeruginosa (P.a) initiates caspase-3-dependent apoptosis in MC38 CRC cell lines. Pyroptosis – characterized by GSDME cleavage, intracellular ROS accumulation, and release of damage-associated molecular patterns, such as HMGB1 – is a form of immunogenic cell death that induces inflammatory cytokine secretion, PD-L1 upregulation on tumor cells, and functional maturation of dendritic cells in vitro. Intratumoral injection of P.a reprogrammed TMEs, increased CD8+ T cell infiltration, and led to synergistic tumor regression, without systemic toxicity when combined with anti-PD-L1 in an MC38 tumor model.
Contributed by Shishir Pant
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.
Author Info: (1) The Fourth Affiliated Hospital of Nanjing Medical University, Nanjing, 210032, China. (2) Department of Neurology, Xindu District People's Hospital of Chengdu, Chengdu, 610500,
Author Info: (1) The Fourth Affiliated Hospital of Nanjing Medical University, Nanjing, 210032, China. (2) Department of Neurology, Xindu District People's Hospital of Chengdu, Chengdu, 610500, China. (3) The Fourth Affiliated Hospital of Nanjing Medical University, Nanjing, 210032, China. (4) Department of Clinical Microbiology, School of Laboratory Medicine, Chengdu Medical College, Clinical IVD Joint Research Center of Chengdu Medical College-Maccura Biotechnology, Chengdu, 610500, China. Sichuan Provincial Engineering Laboratory for Prevention and Control Technology of Veterinary Drug Residue in Animal-Origin Food, Chengdu Medical College, Chengdu, 610500, China. (5) The Fourth Affiliated Hospital of Nanjing Medical University, Nanjing, 210032, China. (6) The Fourth Affiliated Hospital of Nanjing Medical University, Nanjing, 210032, China. (7) Department of Clinical Microbiology, School of Laboratory Medicine, Chengdu Medical College, Clinical IVD Joint Research Center of Chengdu Medical College-Maccura Biotechnology, Chengdu, 610500, China. Sichuan Provincial Engineering Laboratory for Prevention and Control Technology of Veterinary Drug Residue in Animal-Origin Food, Chengdu Medical College, Chengdu, 610500, China. (8) Department of Clinical Microbiology, School of Laboratory Medicine, Chengdu Medical College, Clinical IVD Joint Research Center of Chengdu Medical College-Maccura Biotechnology, Chengdu, 610500, China. Sichuan Provincial Engineering Laboratory for Prevention and Control Technology of Veterinary Drug Residue in Animal-Origin Food, Chengdu Medical College, Chengdu, 610500, China. (9) Taishan Community Health Service Center, Jiangbei New District, Nanjing, 210032, China. (10) Department of Neurology, Xindu District People's Hospital of Chengdu, Chengdu, 610500, China. 501838695@qq.com. (11) Department of Clinical Microbiology, School of Laboratory Medicine, Chengdu Medical College, Clinical IVD Joint Research Center of Chengdu Medical College-Maccura Biotechnology, Chengdu, 610500, China. renke@cmc.edu.cn. Sichuan Provincial Engineering Laboratory for Prevention and Control Technology of Veterinary Drug Residue in Animal-Origin Food, Chengdu Medical College, Chengdu, 610500, China. renke@cmc.edu.cn. (12) The Fourth Affiliated Hospital of Nanjing Medical University, Nanjing, 210032, China. 2608236988@qq.com.
