Pyroptosis as a double-edged sword in colorectal cancer: Molecular mechanisms and therapeutic opportunities.

Colorectal cancer (CRC) is the third most prevalent malignancy globally, with its incidence and mortality rates exhibiting a consistent upward trend. It is commonly diagnosed at an advanced stage, constraining the available therapeutic strategies. Despite extensive research on CRC development and treatment, its specific pathological mechanisms are still not fully understood, and existing therapies face limitations. As one subtype of programmed cell death (PCD), pyroptosis is increasingly connected to complex interactions in cancer. Driven by the gasdermin (GSDM) family, pyroptosis plays context-dependent dual roles in CRC: it can promote tumorigenesis via sustained chronic inflammation and an immunosuppressive tumor microenvironment (TME), or suppress tumors through direct cancer cell killing and antitumor immunity activation. To build on prior work, this review systematically integrates its core molecular mechanisms, context-dependent dual roles, pathway crosstalk (apoptosis, ferroptosis, PANoptosis), and multilevel regulatory networks (gut microbiota, metabolism, epigenetics, non-coding RNAs (ncRNAs)), which have rarely been synthesized cohesively. We explore the clinical implications, with a focus on pyroptosis-based therapeutic strategies (chemotherapy sensitization, natural compounds, nanomedicines, photodynamic therapy (PDT)/sonodynamic therapy (SDT)) and their translational potential, while addressing the critical challenge of balancing their dual effects-an aspect that has not been fully elaborated in previous reviews.