MALT1: The Dual Domains Drive Resistance to Immune Checkpoint Inhibitors

Abstract

A recent research article published by Tao et al. [1] in Nature Cancer pointed out that two domains of Mucosa-Associated Lymphoid Tissue Lymphoma Translocation Protein 1 (MALT1) can promote tumor immune evasion, and that MALT1-targeting antisense oligonucleotides (ASOs) can effectively overcome resistance to immune checkpoint inhibitor (ICI), which are immunotherapy drugs that work by blocking inhibitory immune pathways like PD-1/PD-L1 or CTLA-4 to restore antitumor immunity. These results reveal an innovative method to overcome ICI resistance, offering fresh perspectives for developing cancer immunotherapies.

Cancer immunotherapy refers to therapeutic approaches that harness or enhance the body's immune system to recognize and eliminate tumor cells. With the discovery and characterization of tumor antigens, cancer immunotherapy has gained increasing attention, with research focus evolving from immune cells to tumor cells themselves and their immune microenvironment [2]. Current mainstream immunotherapies, including ICIs, CAR-T cell therapy, and cancer vaccines, have demonstrated promising clinical potential in oncology. Specifically, ICIs block immune checkpoint molecules such as PD-1/PD-L1 and CTLA-4, thereby blocking the suppression of immune cells by tumors and restoring the killing power of immune cells against tumors. Despite their efficacy, ICIs suffer from high rates of primary nonresponse and secondary resistance [3], restricting their widespread use. Studies have identified that the primary mechanisms underlying treatment failure and resistance involve both intrinsic tumor cell drug resistance pathways and the immunosuppressive properties of the tumor microenvironment (TME). Notably, tumor-associated macrophages (TAMs) have attracted much attention due to their unique plasticity and powerful immune regulatory function [4]. By polarizing into M2-type macrophages, TAMs secrete immunosuppressive molecules that inhibit T-cell function, thereby facilitating tumor immune escape.

Originally identified through its chromosomal translocation in MALT lymphoma, MALT1 not only drives lymphomagenesis but also plays broad immunoregulatory roles. As the central component of the CARD11-BCL10-MALT1 (CBM) signaling complex [5], MALT1 orchestrates T/B cell activation and signal transduction through its functional domains. Given its dual roles in promoting tumor immune evasion and lymphocyte dysfunction, MALT1 represents a promising target for overcoming immunotherapy resistance. Using CRISPR screening, Tao et al. created a focused library covering 810 genes in ten core oncogenic pathways. Through CD8⁺ T cell-mediated tumor killing experiments and mouse tumor cell line screening, they found that overexpression of MALT1 in tumor cells significantly enhanced their resistance to CD8⁺ T cell killing. MALT1 regulates the expression level of PD-L1 through its caspase-like activity, leading to immune escape of tumor cells from CD8⁺ T cells. After confirming the interaction between ROQUIN1/2 proteins and Cd274 mRNA using RNA immunoprecipitation experiments, the team further demonstrated that MALT1 stabilizes Cd274 mRNA through proteolytic inactivation of ROQUIN1/2, two key RNA-binding proteins responsible for its degradation. Meanwhile, the death domain of MALT1 binds to BCL10, thereby activating the NF-κB signaling pathway. This cascade promotes the secretion of various immunosuppressive factors, including colony-stimulating factor 1 (CSF1), prostaglandin E2 (PGE2), and chemokine C-X-C motif ligand 1 (CXCL1). These factors play a crucial role in driving the proliferation of TAMs and their polarization towards the M2 phenotype. M2-polarized TAMs are known for their immunosuppressive functions, which include the secretion of anti-inflammatory cytokines and the inhibition of T cell activation. This process ultimately suppresses the function of CD8⁺ T cells, which are key players in antitumor immunity. By inhibiting the cytotoxic activity of CD8⁺ T cells, the tumor microenvironment becomes more immunosuppressive, thereby fostering resistance to ICIs. This highlights the critical role of MALT1 in shaping the immunosuppressive tumor microenvironment and contributing to ICI resistance (Figure 1).

In response to this mechanism, Tao et al. developed ASO24, an antisense oligonucleotide designed to inhibit MALT1. Experimental results showed that ASO24 could significantly reduce the expression levels of MALT1 and PD-L1 in tumor cells, enhance the tumor-killing ability of CD8⁺ T cells, and simultaneously inhibit the proliferation of TAMs and promote their differentiation into M1-type macrophages with antitumor activity. Notably, although MALT1 is expressed in CD8⁺ T cells, CD4⁺ T cells, and regulatory T cells (Tregs), ASO treatment did not significantly alter the activation markers of these immune cells. This finding indicates that systemic administration of ASO does not have a significant negative impact on the function of immune cells, providing an important safety basis for its clinical application.

In summary, this study found that ASOs targeting MALT1 demonstrated significant antitumor activity in various experimental models, especially in enhancing the efficacy of ICIs. This not only provides a new therapeutic approach to address ICI resistance but also opens up a new research direction in the field of cancer immunotherapy. It has significant theoretical and practical implications for promoting the clinical translation of tumor immunotherapy. However, it should be noted that this study had a relatively small clinical sample size and only focused on colorectal and breast cancers. Since the role of MALT1 may vary across different types of cancer, larger-scale validation studies involving multiple cancer types are needed. MALT1 plays a critical role in normal immune cells, including T cells and B cells. Systemic inhibition of MALT1 could potentially lead to immune-related adverse effects, such as an increased risk of autoimmune reactions or infections. While no significant toxicity was observed in the study, the long-term safety profile requires further evaluation. Research shows that targeting MALT1 can overcome ICI resistance, but some tumors may escape treatment through other bypass pathways (such as alternative immune checkpoints or cytokine signals). In the future, strategies combining other targets need to be explored.

Haoze Xie: conceptualization, writing – original draft. Jie Zhang: funding acquisition, writing – review and editing, supervision, resources. Yicheng Chen: funding acquisition, supervision, resources. All authors have read and approved the article.

The authors have nothing to report.

The authors declare no conflicts of interest.