Fig. 3

Pyroptosis cell death and therapeutic strategies in cancer. Triggering cell death as an anti-cancer treatment is a central therapeutic goal. Apoptosis-inducing treatments have achieved great results in promoting tumor growth suppression, but with low immunogenic outcomes. Meanwhile, therapeutic approaches that induce pyroptosis have demonstrated interesting results in some models, with immune response amplification and antigen-specific adaptive immune activation. In some contexts, this mechanism enhances the efficacy of therapeutic approaches, such as immunotherapy and the use of oncolytic viruses (OVs). OVs can infect cancer cells and augment their immunogenicity, being an alternative form of drug delivery, directly targeting cancer cells. Recombinant adeno-associated viruses (rAAV) expressing GSDMD are also able to induce successful anti-tumor immunity mediated by this lytic cell death. This therapeutic approach has demonstrated effective results when in combination with other strategies, being an attractive candidate to overcome immune checkpoint blockade (ICB) resistance. Furthermore, the activation of inflammasomes in response to immunotherapy has gained attention, since its activation by anti-TIM-3 and anti-PD-L1 in DCs, as well as anti-PD-1 in cytotoxic T lymphocytes (CTLs), resulting in the cells’ maturation and activation of an effective bridge to adaptive immune responses. Also, the antigen presentation process itself has been involved in NLRP3-dependent maintenance of a positive feedback loop for enhanced immune response. Controversial results have been reported about this topic, as this strategy is extremely sensitive to the immunogenicity and the tumor immune microenvironment (TIME) characteristics, but results point to a promising role of pyroptosis in the development of new anti-cancer therapies