Attenuated Salmonella-Mediated Delivery of GSDMD Potentiates PD-1 Blockade Therapy against Melanoma
Immunotherapy has emerged as a core therapeutic strategy for melanoma. Programmed death protein 1 (PD-1) is a critical immune checkpoint molecule that restrains host anti-tumor immunity, and therapeutic agents blocking the PD-1 signaling pathway have been widely deployed in clinical practice. Nevertheless, single-agent PD-1 blockade fails to elicit robust clinical responses in the majority of…
Immunotherapy has become a fundamental approach for treating melanoma, as it harnesses the immune system to fight cancer cells. One crucial player in this process is the programmed death protein 1 (PD-1), a checkpoint molecule that inhibits the host's immune response against tumors. Many patients do not benefit from single-agent PD-1 blockade, which has led to the need for more effective treatment combinations.
Gasdermin D (GSDMD) is a pore-forming protein that triggers pyroptosis, a process that aids in eliminating tumor cells. However, it is unclear whether GSDMD can work in tandem with PD-1 blockade to improve results in melanoma patients. To investigate this possibility, researchers created a modified strain of Salmonella bacteria to deliver GSDMD specifically to melanoma cells.
They then tested the combination of this GSDMD-expressing bacterium and an anti-PD-1 antibody in mice with melanoma. The results showed that this combination therapy significantly slowed the growth of tumors compared to using either GSDMD-producing bacteria or anti-PD-1 antibody alone. Mechanisms behind this enhancement included increased expression of GSDMD and the pro-apoptotic protein BAX, reduced PD-1 levels, and higher numbers of CD4 and CD8 T lymphocytes in both the bloodstream and spleen.
Furthermore, the treatment expanded the presence of M1-type tumor-associated macrophages (TAMs), which are known to combat tumors, and shifted these TAMs away from an immunosuppressive M2 phenotype. Simultaneously, the serum levels of pro-inflammatory cytokines TNF- and IFN-gamma rose after the combined intervention. In conclusion, this study demonstrates that delivering GSDMD using attenuated Salmonella bacteria synergizes with anti-PD-1 antibody to generate powerful anti-tumor effects in melanoma mice.
This combination therapy boosts both systemic and intratumoral immune responses, offering a preclinical basis for developing novel therapeutic strategies against melanoma.
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