Crosstalk between hypoxia-induced pyroptosis and immune escape in cancer: From mechanisms to therapy.

ABSTRACT

Pyroptosis can be triggered through both canonical and non-canonical inflammasome pathways, involving the cleavage of gasdermin (GSDM) protein family members, like GSDMD and GSDME. The impact of pyroptosis on tumors is nuanced, because its role in regulating cancer progression and anti-tumor immunity may vary depending on the tumor type, stage, location, and immune status. However, pyroptosis cannot be simply categorized as promoting or inhibiting tumors based solely on whether it is acute or chronic in nature. The interplay between pyroptosis and cancer is intricate, with some evidence suggesting that chronic pyroptosis may facilitate tumor growth, while the acute induction of pyroptosis could stimulate anti-cancer immune responses. Tumor hypoxia activates hypoxia inducible factor (HIF) signaling to modulate pyroptosis and immune checkpoint expression. Targeting this hypoxia-pyroptosis-immune escape axis could be a promising therapeutic strategy. This review highlights the complex crosstalk between hypoxia, pyroptosis, and immune evasion in the TME.