<p>Pyroptosis, a form of pro inflammatory programmed cell death, distinguishes itself from the usual programmed cell death or apoptosis. With its dual role in tumor microenvironment, this process acts as a pivotal player in tumor biology. This review discusses the existing known molecular mechanism of pyroptosis, while highlighting the gaps in existing knowledge in understanding the signalling pathways and regulation. Pyroptosis is often related to synergistic to other forms of cellular death including necroptosis and ferroptosis and we have highlighted this interrelationship’s connecting link between pyroptosis and tumor microenvironment. We further explored the concept of “hot” and “cold” tumors, the biomarkers and threshold values that classify them as hot as well as cold and the prognostic implications and survival probability of these two tumor phenotypes in different types of cancers. We have further explored the classification of immunologically “hot” and “cold” tumor phenotypes through biomarkers and threshold criteria suggest by a number of studies that classify them as hot as well as cold, highlighting their potential prognostic significance and treatment strategies. This review further covers therapeutic strategies aimed at modulating pyroptosis in tumor microenvironment aiming at improving the patient’s outcome. The drugs that mediate pyroptosis modulation as well as their mechanism of action are reviewed. Beyond linking the pyroptotic mechanism to therapeutics, there is the unique presentation of Comparative Toxicogenomic Database or CTD based drug-gene network in order to identify less explored chemical modulators of pyroptosis, having potential translational relevance. Notably, this CTD-driven network pharmacology identifies both well-characterized as well as relatively limited explored compounds that interact with the key pyroptotic regulators, hence unveiling the existing loopholes in current experimental coverage and highlighting compounds that needs further exploration in future studies targeting providing a more context-specific mechanism of pyropytosis and their translational relevance in the field of oncology. This discussion emphasizes pyroptosis as a complex yet promising avenue for cancer therapeutics with the deeper mechanistic insights that are yet to be explored.</p> Graphical Abstract <p></p>