The Toxoplasma surface SRS14A promotes ASC ubiquitination to suppress AIM2 inflammasome and tumor immunity

Toxoplasma gondii (T. gondii), a globally distributed obligate intracellular protozoan parasite, modulates host immunity through mechanisms that remain incompletely elucidated. Here, we demonstrate that the Toxoplasma surface SRS14A directly interacts with the CARD domain of ASC. Overexpression of SRS14A inhibits AIM2 inflammasome activation in macrophages, whereas infection with the srs14a-knockout strain (Δsrs14a) potentiates AIM2 inflammasome activity, leading to mitochondrial dysfunction and cellular damage. Mechanistically, SRS14A induces K63-linked ubiquitination of ASC's CARD domain, promoting its proteasomal degradation. Notably, Δsrs14a infection significantly attenuates tumor progression, concomitant with enhanced CD8⁺ T cell infiltration, reduced regulatory T cells (Treg) frequency, and M1 phenotype polarization. Within the tumor microenvironment (TME), Δsrs14a infection elevates AIM2 inflammasome activity, further implicating SRS14A in tumor immune modulation. Our findings establish SRS14A as a critical suppressor of inflammasome signaling, linking T. gondii surface antigens, AIM2 inflammasome activation, and tumor immune evasion. This study provides novel insights into parasite-host interaction and tumor immunoregulation, advancing our understanding of pathogen-mediated immune subversion.