MALT1 protease inhibition restrains glioblastoma progression by reversing tumor-associated macrophage-dependent immunosuppression in mice

MALT1 protease is an intracellular signaling molecule that promotes tumor progression via cancer cell-intrinsic and cancer cell-extrinsic mechanisms. MALT1 has been mostly studied in lymphocytes, and little is known about its role in tumor-associated macrophages. We show that MALT1 is expressed in glioblastoma (GBM)-associated macrophages. Mechanistically, GBM tumor cells induce a MALT1-NF-κB signaling axis in macrophages, leading to enhanced macrophage migration and polarization toward an immunosuppressive (‘M2-like’) phenotype. Inactivation of MALT1 protease promotes transcriptional reprogramming that reduces migration and restores a macrophage anti-tumor ‘M1-like’ phenotype. Preclinical in vivo analysis shows that MALT1 inhibitor treatment results in immuno-reactivity of GBM-associated macrophages and reduced GBM tumor growth. The addition of MALT1 inhibitor to temozolomide reduces immunosuppression in the tumor microenvironment, indicating that pharmacological inhibition of MALT1 protease may enhance the efficacy of chemotherapeutic. Thus, our findings suggest that MALT1 protease inhibition represents a promising macrophage-targeted immunotherapeutic strategy for the treatment of GBM. MALT1 protease is an intracellular signalling molecule that regulates adaptive immune responses and has been implicated in the pathogenesis of hematologic and solid malignancies. Here, the authors investigate the function of MALT1 in tumor-associated macrophages. In preclinical models of glioblastoma (GBM), tumor cells induce MALT1 and NFKb signaling activation, driving macrophage polarization towards a tumor-supportive phenotype, and MALT1 inhibition enhances macrophage immunoreactivity, suppressing GBM tumor growth.