Pyroptosis in cancer nanotherapy: Molecular mechanisms and advanced nanosystems (Review)

Pyroptosis is a form of programmed cell death characterized by activation of inflammasome complexes and caspase signaling cascades, ultimately leading to the cleavage and activation of pore‑forming executioners such as gasdermin D (GSDMD), ‑E and ‑B. Accumulating evidence indicates that pyroptosis induction in cancer cells exerts potent antitumor effects. As a result, recent therapeutic strategies such as cancer nanotherapy have increasingly focused on harnessing pyroptotic cell death to improve cancer treatment outcomes. This review aimed to explore recent advances in nanotechnology‑based approaches designed to induce pyroptosis in cancer cells, with an emphasis on their potential to enhance antitumor immunity and overcome treatment resistance. It explored four distinct nanoplatforms: i) Chemo‑photodynamic systems that trigger GSDME‑mediated death by generating reactive oxygen species; ii) magneto‑plasmonic nanoparticles that use GSDME activation to modulate the tumor microenvironment, turning 'cold' tumors 'hot'; iii) bioorthogonal chemical delivery tools leveraging click chemistry for site‑specific gasdermin release; and iv) nano‑CRISPR activation scaffolds designed to boost GSDME expression and work alongside cisplatin. Beyond these platforms, the present review highlights how immune cell‑derived granzymes and interferon‑γ drive vital downstream pyroptotic pathways via GSDME and GSDMB activation. Lastly, the review weighs clinical risks, such as chronic systemic inflammation and tumor‑promoting environments, providing a realistic perspective on how to safely progress these preclinical nanotherapies into selective, effective clinical immunotherapies.