Breaking the Defensive Line: Colorectal Cancer’s Epigenetic Escape

By: Jared Von C. Santiago | Fosmid

Colorectal cancer (CRC), which develops in the inner lining of the colon or rectum, is the fourth leading cause of cancer-related deaths among Filipinos. Although cancer is often seen as an unstoppable force to be reckoned with, tumor cells must first overcome the body’s most potent line of defense — the immune system. As we observe National Colorectal Cancer Month, a recent study by Lakatos and colleagues (2025) suggests that CRC tumor cells' ability to evade the body’s immune system may emerge much earlier in tumor development than scientists previously believed.

Traditionally, CRC development  has been modeled as a sequential process of tumorigenesis, in which tumors arise through a gradual accumulation of genetic alterations. In this model, clones with selective growth advantages expand over time until the clone with the greatest selective advantage eventually dominates the tumor. However, recent advances support the Big Bang model of CRC tumor growth, which proposes that after the initial transformation, tumors grow rapidly while simultaneously generating numerous genetically distinct subclones early in development. As a result, genetically diverse groups of cancer cells, a phenomenon known as intratumoral heterogeneity (ITH) may emerge much earlier than previously thought, shaping how tumors interact with the immune system.

During the early stages of cancer development, immune cells such as natural killer (NK) cells and Cytotoxic (CD8+) T cells can recognize and destroy abnormal cells. These immune cells are particularly effective against highly immunogenic cancer cells, which display abnormal proteins or neoantigens and are therefore more visible to the immune system. However, some cancer cells evade the immune defense through a process called immunoediting, in which less immunogenic tumor cells persist and proliferate amidst immune defenses.

Tumors primarily evade immune defenses by evading immune recognition or creating an immunosuppressive tumor microenvironment (TME). Lakatos and colleagues discovered that CRC tumors may avoid immune detection through epigenetic changes called somatic chromatin accessibility alterations (SCAAs). These alterations modify how accessible chromatin is to the transcriptional machinery, reducing access to promoter regions of antigen-presenting genes (APGs). As a result, genes involved in antigen presentation are underexpressed, making tumor cells less visible to the immune system. The study identified 45 SCAAs affecting Antigen-presentation gene promoters, 93% of which involved losses of chromatin accessibility, indicating widespread epigenetic silencing of antigen presentation.

Notably, these chromatin changes appear to occur early in tumor development. By integrating genomic, transcriptomic, and chromatin accessibility data from hundreds of tumor glands, the researchers found that immune escape mechanisms can arise near the onset of CRC development, supporting the Big Bang model that suggests immune-evasive traits may emerge early and persist as the tumor expands. 

These findings carry important insights for cancer research and treatment, as many immunotherapies target genetic pathways of immune escape. However, if tumors suppress antigen presentation through epigenetic mechanisms, they may remain less detectable to immune cells even with immunotherapeutic treatments. Understanding these chromatin-based escape strategies may help explain why some CRCs respond poorly to immunotherapy and could guide the development of treatments that restore immune recognition.