Study Finds That CBX4 Is a Key Epigenetic Regulator in Cancer Immunotherapy

Immunotherapy, especially immune checkpoint blockade (ICB), which triggers T cell responses, has become a major approach for treating various cancers. Although cancer immunotherapy can produce durable responses, many patients either fail to benefit from it, known as primary resistance, or relapse after a period of remission, known as acquired resistance. This highlights the urgent need to identify cellular and molecular targets for advanced immunotherapeutic strategies.

Recently, researchers published a study online in the Journal of Clinical Investigation titled “In vivo CRISPR screens identify CBX4 as an epigenetic regulator for cancer immunotherapy”. The study shows that targeting CBX4 induces endogenous retrovirus (ERV) expression and activates RIG-I signaling, thereby enhancing ICB therapy. In addition, CBX4 may serve as a biomarker for stratifying cancer patients receiving immune checkpoint blockade therapies, such as anti-PD-1 or anti-PD-L1 treatment, and may be used to predict immunotherapeutic response and clinical efficacy.

The clinical efficacy of ICB therapy depends on the proper function of CD8+ T cells and coordinated intercellular interactions within the tumor microenvironment. These interactions are essential for initiating and sustaining T cell responses, promoting the formation of durable memory T cells, overcoming resistance, and achieving favorable therapeutic outcomes. However, T cells do not function autonomously in carrying out their effector activities.

The initiation and maintenance of T cell responses are regulated by innate immune responses. The role of innate immunity in T cell activation involves complex signaling pathways, including cytokine production and receptor-ligand interactions. Strategies that enhance innate immune responses may synergize with ICB therapy to strengthen the effector function of CD8+ T cells and improve overall cancer treatment outcomes.

Emerging evidence suggests that under immune pressure, tumors acquire traits that undermine antitumor immunity through highly plastic epigenetic reprogramming, leading to immune evasion and resistance to ICB therapy. Epigenetic reprogramming, including DNA methylation, histone modification, and non-coding RNA regulation, refers to heritable changes in gene expression that do not involve alterations in the underlying DNA sequence. Understanding and targeting these epigenetic crosstalk pathways provides unique opportunities for selective therapeutic intervention. However, the complexity and heterogeneity of epigenetic alterations within tumors pose major challenges to identifying core epigenetic drivers.

In this study, the researchers identified CBX4 as an epigenetic target involved in immune evasion and resistance to immunotherapy. CBX4 was found to accumulate in tumor cells and in immunosuppressive tumor-associated macrophage subsets among patients who did not respond to anti-PD-1 therapy.

Figure 1. Schematic illustration of the mechanism. (Ma Z, et al., 2026)

Targeting CBX4 derepresses endogenous retroelements marked by H3K9me3 and H3K27me3, such as RLTR4-MM-int, triggering cytoplasmic RNA-sensing pathways and subsequent type I interferon responses, ultimately leading to a strongly inflammatory tumor microenvironment. By reversing the epigenetic silencing of retrotransposons and reshaping the immune tumor microenvironment, this study establishes CBX4 as an epigenetic immune checkpoint, providing a promising therapeutic target for enhancing tumor immunogenicity and overcoming resistance to immunotherapy.