Immune checkpoint inhibitor (ICI) therapy has demonstrated therapeutic benefits and prolonged survival in cancer patients. However, most patients either fail to respond to ICI therapy or develop resistance to it.
Functional genomic screens using CRISPR-Cas9 technology have identified multiple tumor-intrinsic drivers associated with ICI resistance. Despite these advances, the practical application of these findings remains limited. In addition to intrinsic mechanisms, the suppressive tumor immune microenvironment (TiME), characterized by the presence of infiltrating tumor-associated macrophages (TAMs), has become a major obstacle to effective outcomes of ICI therapy. TAMs exhibit a high degree of plasticity and are able to polarize into multiple subsets with immunosuppressive functions. Current strategies targeting macrophages, including macrophage depletion or interference with their pro-tumor polarization, have shown limited therapeutic efficacy in clinical trials. Therefore, it is necessary to identify new molecular targets in the tumor microenvironment to overcome resistance to immune checkpoint inhibitor (ICI) therapy.
Recently, a research team from the School of Basic Medical Sciences of Tsinghua University in China published a research paper titled "Targeting both death and paracaspase domains of MALT1 with antisense oligonucleotides overcomes resistance to immune-checkpoint inhibitors" in Nature Cancer, a subsidiary of Nature. The study found that MALT1 plays a dual role in promoting tumor immune escape through its death domain and paracaspase domain. Using antisense oligonucleotides (ASO) to target these two domains of MALT1 can overcome tumor resistance to immune checkpoint inhibitors.
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The MALT1 protein is required for lymphocyte activation and lymphomagenesis. Currently, targeting the paracaspase domain activity of MALT1 has been explored for the treatment of B-cell lymphoma and solid tumors. Although the role of MALT1 in promoting cancer cell proliferation has been studied, its role in immune escape is still unclear.
In this latest study, the research team revealed that MALT1 promotes immune escape through a dual mechanism. On the one hand, MALT1 protects CD274 mRNA (encoding PD-L1) from degradation by cleaving ROQUIN1 and ROQUIN2 through its paracaspase domain, thereby upregulating PD-L1 expression levels. On the other hand, MALT1 promotes the proliferation and M2 polarization of tumor-associated macrophages (TAMs) through its death domain, thereby generating an inhibitory tumor immune microenvironment.
Figure 1. Current model of MALT1 in cancer immune evasion. (Tao Y, et al., 2025)
Based on the above findings, the research team designed antisense oligonucleotides (ASOs) that can simultaneously target the paracaspase domain and death domain of MALT1, which can inhibit the expression of PD-L1 in tumor cells derived from cancer patients and inhibit the proliferation and M2 polarization of tumor-associated macrophages isolated from cancer patients. In a mouse solid tumor model, ASOs targeting MALT1 can overcome tumor resistance to immune checkpoint inhibitors.
Overall, this study demonstrates that targeting MALT1 is a potential strategy to overcome resistance to immune checkpoint inhibitors.
Reference
- Tao Y, et al. Targeting both death and paracaspase domains of MALT1 with antisense oligonucleotides overcomes resistance to immune-checkpoint inhibitors. Nature Cancer, 2025: 1-16.