Therapeutic targeting of MALT1 in oncology: Mechanism, inhibitor development, and clinical prospects

MALT1, a multifunctional protease molecule, plays a pivotal role in the adaptive immunity by regulating immune cell survival, proliferation and activation through the nuclear transcription factor-κB (NF-κB) signaling pathway by scaffold and protease activities. Aberrant activation of MALT1 is implicated in the pathogenesis of hematologic malignancies, particularly diffuse large B-cell lymphoma, and select solid tumors. Emerging research studies highlight MALT1 inhibitors as promising therapeutic agents for B-cell malignancies, with several candidates demonstrating preclinical and clinical efficacy. Notably, agents such as safimaltib (JNJ-67856633) have shown manageable safety profiles and preliminary antitumor activity in early-phase trials for relapsed/refractory B-cell malignancies. However, MALT1-targeted therapy poses a dual challenge: although inhibiting oncogenic signaling and tumor cell proliferation, it also disrupts immunosuppressive Treg function, risking autoimmune toxicity by compromising the tumor microenvironment. This review systematically analyzes MALT1's oncogenic roles across cancers, clarifies inhibitor mechanisms, and evaluates translational challenges and strategic opportunities for precision oncology and combination immunotherapy.