biostudies-literatureLeuzzi GNIDCR NIH HHSNCI NIH HHSNIH HHSNIGMS NIH HHS861-881.e32https://www.ebi.ac.uk/biostudies/studies/S-EPMC10980358biostudies-literatureUnknown187(4)Genomic instability can trigger cancer-intrinsic innate immune responses that promote tumor rejection. However, cancer cells often evade these responses by overexpressing immune checkpoint regulators, such as PD-L1. Here, we identify the SNF2-family DNA translocase SMARCAL1 as a factor that favors tumor immune evasion by a dual mechanism involving both the suppression of innate immune signaling and the induction of PD-L1-mediated immune checkpoint responses. Mechanistically, SMARCAL1 limits endogenous DNA damage, thereby suppressing cGAS-STING-dependent signaling during cancer cell growth. Simultaneously, it cooperates with the AP-1 family member JUN to maintain chromatin accessibility at a PD-L1 transcriptional regulatory element, thereby promoting PD-L1 expression in cancer cells. SMARCAL1 loss hinders the ability of tumor cells to induce PD-L1 in response to genomic instability, enhances anti-tumor immune responses and sensitizes tumors to immune checkpoint blockade in a mouse melanoma model. Collectively, these studies uncover SMARCAL1 as a promising target for cancer immunotherapy.CellSMARCAL1 is a dual regulator of innate immune signaling and PD-L1 expression that promotes tumor immune evasion.PMC10980358R44 GM123869R01 CA266446R35 CA197745R01 DE031873S10 OD012351K99 CA273538S10 OD032433P30 CA013696S10 OD020056R01 CA197774R37 CA258829R01 CA227450R44 DE029633R01 CA280414S10 OD021764Venters BJGao JGuccione EGhasemzadeh ASun LLeuzzi GHuang JWHickman ARIzar BMao WBaer RTaglialatela AChen XCuella-Martin RRialdi AFirestone TMThakar TNambiar TSGopinath SLu CCiccia AKesner JSVasciaveo ALi YKeogh MCVaitsiankova ACalifano AHo PHayward SBAdeleke OADrake CGHebrard MGuerois RfalseSMARCAL1 is a dual regulator of innate immune signaling and PD-L1 expression that promotes tumor immune evasion.Genomic instability can trigger cancer-intrinsic innate immune responses that promote tumor rejection. However, cancer cells often evade these responses by overexpressing immune checkpoint regulators, such as PD-L1. Here, we identify the SNF2-family DNA translocase SMARCAL1 as a factor that favors tumor immune evasion by a dual mechanism involving both the suppression of innate immune signaling and the induction of PD-L1-mediated immune checkpoint responses. Mechanistically, SMARCAL1 limits endogenous DNA damage, thereby suppressing cGAS-STING-dependent signaling during cancer cell growth. Simultaneously, it cooperates with the AP-1 family member JUN to maintain chromatin accessibility at a PD-L1 transcriptional regulatory element, thereby promoting PD-L1 expression in cancer cells. SMARCAL1 loss hinders the ability of tumor cells to induce PD-L1 in response to genomic instability, enhances anti-tumor immune responses and sensitizes tumors to immune checkpoint blockade in a mouse melanoma model. Collectively, these studies uncover SMARCAL1 as a promising target for cancer immunotherapy.2024-01-01T00:00:00Z2024 Feb2026-06-03T04:48:27.092Z2025-04-04T00:16:13.667ZS-EPMC109803583830164610.1016/j.cell.2024.01.008