Harnessing the death switch: Empowering cancer therapy by modulating the apoptosis-pyroptosis transition

Overcoming therapeutic resistance mediated by apoptosis evasion represents a critical challenge in cancer treatment. Pyroptosis, an inflammatory form of regulated cell death, provides a promising alternative approach capable of stimulating robust anti-tumor immunity and converting immunologically inert ("cold") tumors into immunologically active ("hot") microenvironments. Importantly, these cell death pathways are not isolated but are interconnected through dynamic molecular switches that determine cellular fate. This review systematically examines the intricate molecular crosstalk between cell death modalities, with particular emphasis on the regulatory roles of the caspase-3/GSDME and caspase-8/GSDMD axes. Current evidence demonstrates that caspase family members, primarily associated with apoptosis, can selectively cleave gasdermin proteins, facilitating a transition from non-inflammatory apoptotic signaling to inflammatory pyroptotic events. We further analyze how inflammasomes, post-translational modifications, and the STING-NF-κB pathway precisely regulate this transition. Through integrated bioinformatic analysis, we identified novel hub genes (e.g., PRKAR1A, PPP2CA, FOSL2) and microRNA networks at the apoptosis-pyroptosis interface, providing novel insights and potential therapeutic targets. Exploiting this 'death switch' offers a novel therapeutic framework through three principal strategies: (1) inducing pyroptosis to eliminate apoptosis-resistant cells, (2) utilizing pyroptosis-induced inflammation to enhance immune checkpoint inhibitor efficacy, and (3) developing targeted therapeutics that directly modulate these switch molecules. Although controlling pyroptosis-associated inflammation remains challenging, understanding and manipulating the apoptosis-to-pyroptosis transition provides an innovative approach to overcome drug resistance and develop more effective cancer treatments.