通过治疗性拮抗mSWI/SNF染色质重塑复合物重编程抗肿瘤免疫

Beyond its tumor cell-intrinsic role in transcription factor driven cancers, emerging studies indicate that the mammalian SWI/SNF (mSWI/SNF) chromatin remodeling complex also plays critical roles in immune cell function, raising the possibility that SWI/SNF antagonism may modulate antitumor immunity in addition to its direct effects on tumor cells. However, these studies have largely been restricted to ex vivo manipulation of effector T cells in adoptive cell therapy settings, owing in part to the historical lack of selective, systemically bioavailable SWI/SNF antagonists. Here, we leveraged two recently developed, selective, orally bioavailable SWI/SNF ATPase antagonists, the PROTAC-based degrader AU-24118 and the catalytic ATPase inhibitor FHD-286, to enable systemic mSWI/SNF antagonism and allow comprehensive interrogation of mSWI/SNF function across tumor, myeloid, and lymphoid compartments under physiologically relevant conditions. We found that mSWI/SNF antagonism elicits potent, immune-dependent antitumor activity across multiple syngeneic tumor models and remains effective in tumors lacking Smarca2/4 , demonstrating that therapeutic efficacy in these settings is mediated through the immune compartment rather than tumor cell-intrinsic vulnerabilities. Temporal immune profiling by single-cell RNA sequencing and flow cytometry revealed that mSWI/SNF antagonism rapidly depletes immunosuppressive populations within the tumor microenvironment (TME), followed by expansion of functional immune effector cells. Consistently, systemic SWI/SNF antagonism synergizes with immune checkpoint blockade therapy without inducing systemic toxicity. Mechanistically, integrative ATAC-seq, ChIP-seq, and RNA-seq analyses demonstrated that SWI/SNF antagonism induces a global collapse of chromatin accessibility in immunosuppressive populations at regulatory elements occupied by lineage-defining transcription factors thereby extinguishing transcriptional programs that sustain immunosuppression. Collectively, these findings identify a targetable epigenetic dependency in immunosuppressive populations within the tumor microenvironment and establish mSWI/SNF antagonism as a precision strategy to overcome immunosuppressive TME-driven resistance to cancer immunotherapy.