Targeting both death and paracaspase domains of MALT1 with antisense oligonucleotides overcomes resistance to immune-checkpoint inhibitors.

Targeting MALT1's paracaspase activity has been explored for B cell lymphoma and solid tumors. While the role of MALT1 in promoting cancer cell proliferation has been investigated, its involvement in immune evasion is unclear. Here we report that MALT1 promotes immune evasion through its paracaspase and death domain. In a paracaspase-dependent manner, MALT1 protects CD274 mRNA from degradation by its cleavage of ROQUIN1 and ROQUIN2. In a death-domain-dependent manner, MALT1 promotes the proliferation and polarization of tumor-associated macrophages to generate an immunosuppressive tumor microenvironment. Targeting MALT1 with antisense oligonucleotides inhibits PD-L1 expression in patient-derived tumor cells and suppresses the proliferation and M2-like polarization of tumor-associated macrophages isolated from patients with cancer. In preclinical models of solid tumors in female mice, treatment with MALT1 antisense oligonucleotides overcomes resistance to immune-checkpoint inhibitors. Together, our study demonstrates that targeting MALT1 is a potential strategy to overcome immune-checkpoint inhibitor resistance.