City of Hope Researchers Uncover NAT10-MYC Pathway Driving Immunotherapy Resistance in Colorectal Cancer
Key Insights
City of Hope (search) scientists identified a previously unrecognized MYC (search)-NAT10 (search)-autophagy axis that explains why many colorectal tumors, particularly microsatellite-stable (MSS) subtypes, remain resistant to immunotherapy.
Elevated NAT10 (search) activity promotes immune evasion by enhancing autophagy-mediated loss of MHC class I molecules, creating immune-cold tumor environments with reduced responses to checkpoint inhibitors.
In preclinical models, disrupting the NAT10 (search)-MYC (search) pathway restored immune signaling, increased immune cell infiltration, and led to substantial tumor regression when combined with immune checkpoint blockade.
City of Hope (search) researchers will present new findings at the AACR Annual Meeting 2026 identifying a molecular pathway that helps explain why many colorectal cancers remain stubbornly resistant to immunotherapy. The discovery, centered on the RNA-modifying enzyme NAT10 (search) and its interaction with the oncogene MYC (search), opens a potential new therapeutic avenue for patients with microsatellite-stable (MSS) tumors—the majority of colorectal cancer (search) cases that currently do not benefit from immune checkpoint inhibitors.
The research is among 103 sessions featuring City of Hope (search) expertise at the American Association for Cancer Research annual meeting, held April 17–22, 2026.
Uncovering the MYC (search)-NAT10 (search)-Autophagy Axis
The investigative team focused on NAT10 (search), an RNA-modifying enzyme, and its functional relationship with MYC (search), a well-established oncogenic driver in colorectal cancer (search). They discovered that elevated NAT10 activity promotes immune evasion through a specific mechanism: enhancing autophagy-mediated loss of MHC class I molecules. These molecules are essential for immune cells to recognize and target cancer cells; their depletion effectively renders tumors invisible to the immune system.
High NAT10 (search) expression was associated with immune-cold tumor environments—characterized by little to no immune cell activity—and reduced predicted responses to immune checkpoint inhibitors. These effects were especially pronounced in MSS colorectal cancers, which account for the majority of cases and remain largely resistant to current immunotherapy approaches.
“These findings help explain why many colorectal tumors remain resistant to immunotherapy. By targeting this newly identified pathway, we may be able to improve immune recognition of tumors and expand the benefit of immunotherapy to more patients,” said Junyong Weng, Ph.D., the study’s presenting author and a City of Hope (search) visiting scholar.
Preclinical Validation and Therapeutic Implications
In preclinical models, disrupting the NAT10 (search)-MYC (search) pathway produced striking results. The intervention restored immune signaling, increased immune cell infiltration into tumors, and enhanced responses to immunotherapy. When combined with immune checkpoint blockade, the approach resulted in substantial tumor regression.
Ajay Goel, Ph.D., AGAF, senior author on the study and chair of City of Hope (search)’s Department of Molecular Diagnostics and Experimental Therapeutics, emphasized the translational significance: “Our findings identify a previously unrecognized MYC (search)-NAT10 (search)-autophagy axis as a mechanism of immune evasion and immunotherapy resistance in colorectal cancer (search). MYC is a key driver of this disease but remains difficult to target therapeutically, while autophagy is essential for normal cell survival. Our study suggests that targeting tumor-specific NAT10 upregulation may offer a more selective strategy to suppress aberrant autophagy, prevent MHC-I loss and improve antitumor immune recognition.”
The selectivity point is critical. Because MYC (search) has proven notoriously difficult to drug directly, and autophagy is a fundamental cellular process required for normal cell survival, therapeutically targeting NAT10 (search)—which appears specifically upregulated in tumor cells—may provide a more precise intervention strategy with a favorable therapeutic window.
Broader Context at AACR 2026
The NAT10 (search)-MYC (search) findings are part of a broader City of Hope (search) presence at AACR 2026. Other notable presentations include AI-driven analysis revealing distinct microbiome patterns linked to early-onset colorectal cancer (search) (abstract 3993), preclinical work identifying eIF4A1 (search) as a metabolic vulnerability in acute myeloid leukemia (search) (abstract 4037), and new AI foundation models improving prediction of immune targets for cancer vaccines and therapies (abstract 1298).
In a major symposium, Stephen J. Forman, M.D., will discuss first-line CAR T cell therapy for adults with acute lymphoblastic leukemia (search), while Robert R. Jenq, M.D., will present evidence on how the microbiome influences CAR T cell patient outcomes in an Advances in Diagnostics and Therapeutics session.
The collective research underscores City of Hope (search)’s translational focus. “This study shows the power of looking at cancer as an interconnected system, not just a single target,” said Rui Su, Ph.D., senior author on the related AML metabolic study, reflecting an institutional philosophy that spans multiple presentations at the meeting.