Gasdermins (GSDMs) are key proteins involved in pyroptosis, a form of programmed cell death critical for immune responses, particularly in combating infections and tumors. GSDMs, including GSDMA/B/C/D, GSDME (DFNA5), and DFNB59 (pejvakin, PJVK), play a pivotal role in cell membrane perforation, immune factor release, and cell death. These proteins are activated by caspases and granzymes through inflammasome signaling pathways, contributing to immune defense against pathogens and cancers. GSDMs have two distinct domains: the C-terminal inhibitory domain (CT) and the N-terminal effector domain (NT). Under normal conditions, these domains inhibit each other, but upon activation by pathogenic or damaging signals, caspases or granzymes cleave GSDMs, separating them into N-terminal and C-terminal segments. These segments then oligomerize, forming pores in the cell membrane, leading to the release of inflammatory molecules and pyroptosis. Pyroptosis, characterized by inflammation, is facilitated by GSDM proteins. It manifests abruptly, eliciting a heightened inflammatory reaction compared to other programmed cell death mechanisms. In 2015, the segmentation of GSDMD into N-terminal and C-terminal domains by caspase-1 was discovered, revealing the pyroptosis process. The free N-terminal domain of GSDMD forms a channel in the cell membrane, causing an influx of water into the cell, altering osmotic balance, and leading to cellular expansion and membrane rupture. Internal inflammation-inducing agents, such as interleukin-18 (IL-18) and IL-1β, disperse, triggering an inflammatory reaction and forming an inflammatory microenvironment. Immunotherapy has become a pivotal role in tumor treatment, with major modalities including oncolytic virus therapies, cancer vaccines, adoptive cell transfer, cytokine therapies, and immune checkpoint inhibitors. Studies demonstrate that combining programmed death-1/programmed death ligand 1 (PD-1/PD-L1) checkpoint blockade immunotherapies with the anti-angiogenic agent bevacizumab significantly enhances overall survival in non-small cell lung cancer (NSCLC) patients. However, challenges persist, including limited applicability, unpredictable clinical effects, and innate or adaptive drug resistance issues, impeding broader clinical adoption of immunotherapy. Resistance to innate immunotherapy may stem from a lack of intrinsic immune response to specific developing tumors, often observed in patients with systemic immunosuppression. Acquired immunotherapy resistance primarily reflects the tumor entering a therapeutic equilibrium state, closely tied to the intrinsic immune escape mechanisms of tumors. Pyroptosis, mediated by GSDM-related signaling pathways, not only induces tumor cell pyroptosis but also mitigates drug resistance and adverse reactions in treatment. Research suggests that pyroptosisGasdermins (GSDMs) are key proteins involved in pyroptosis, a form of programmed cell death critical for immune responses, particularly in combating infections and tumors. GSDMs, including GSDMA/B/C/D, GSDME (DFNA5), and DFNB59 (pejvakin, PJVK), play a pivotal role in cell membrane perforation, immune factor release, and cell death. These proteins are activated by caspases and granzymes through inflammasome signaling pathways, contributing to immune defense against pathogens and cancers. GSDMs have two distinct domains: the C-terminal inhibitory domain (CT) and the N-terminal effector domain (NT). Under normal conditions, these domains inhibit each other, but upon activation by pathogenic or damaging signals, caspases or granzymes cleave GSDMs, separating them into N-terminal and C-terminal segments. These segments then oligomerize, forming pores in the cell membrane, leading to the release of inflammatory molecules and pyroptosis. Pyroptosis, characterized by inflammation, is facilitated by GSDM proteins. It manifests abruptly, eliciting a heightened inflammatory reaction compared to other programmed cell death mechanisms. In 2015, the segmentation of GSDMD into N-terminal and C-terminal domains by caspase-1 was discovered, revealing the pyroptosis process. The free N-terminal domain of GSDMD forms a channel in the cell membrane, causing an influx of water into the cell, altering osmotic balance, and leading to cellular expansion and membrane rupture. Internal inflammation-inducing agents, such as interleukin-18 (IL-18) and IL-1β, disperse, triggering an inflammatory reaction and forming an inflammatory microenvironment. Immunotherapy has become a pivotal role in tumor treatment, with major modalities including oncolytic virus therapies, cancer vaccines, adoptive cell transfer, cytokine therapies, and immune checkpoint inhibitors. Studies demonstrate that combining programmed death-1/programmed death ligand 1 (PD-1/PD-L1) checkpoint blockade immunotherapies with the anti-angiogenic agent bevacizumab significantly enhances overall survival in non-small cell lung cancer (NSCLC) patients. However, challenges persist, including limited applicability, unpredictable clinical effects, and innate or adaptive drug resistance issues, impeding broader clinical adoption of immunotherapy. Resistance to innate immunotherapy may stem from a lack of intrinsic immune response to specific developing tumors, often observed in patients with systemic immunosuppression. Acquired immunotherapy resistance primarily reflects the tumor entering a therapeutic equilibrium state, closely tied to the intrinsic immune escape mechanisms of tumors. Pyroptosis, mediated by GSDM-related signaling pathways, not only induces tumor cell pyroptosis but also mitigates drug resistance and adverse reactions in treatment. Research suggests that pyroptosis