New immunotherapy strategy overcomes resistance in colorectal cancer treatment

Researchers at the Icahn School of Medicine at Mount Sinai and the Mount Sinai Tisch Cancer Center have identified a promising new strategy to overcome resistance to immunotherapy in colorectal cancer, one of the leading causes of cancer-related deaths worldwide. The findings, published in Cell Reports Medicine (10.1016/j.xcrm.2026.102786 ), reveal that restoring communication between key immune cells can dramatically improve the body's ability to eliminate tumors.

Immunotherapy has transformed cancer care, but many patients with colorectal cancer, particularly those with treatment-resistant disease, do not benefit from currently available approaches. The Mount Sinai-led study found that successful anti-tumor responses depend not only on activating cancer-fighting T cells, but also on coordinated interactions between T cells and myeloid cells, including macrophages, which are the specialized white blood cells that detect, engulf, and destroy cells that can cause disease.

Our findings show that it's not enough to simply activate the immune system. You also need to restore the communication between immune cells so they can work together effectively against the tumor."

Nina Bhardwaj, MD, PhD, co-senior author, Director of Immunotherapy and Ward-Coleman Chair in Cancer Research, and Professor of Medicine (Hematology and Medical Oncology), and Urology, at the Icahn School of Medicine

Using advanced preclinical models and single-cell analyses, the research team identified key features of immunotherapy resistance, including exhausted T cells and the presence of suppressive macrophages that block immune activity. They then tested a novel combination approach targeting multiple immune checkpoint proteins (PD-1, CTLA-4, and LAG3) alongside TREM2, a marker of immunosuppressive macrophages.

"This study highlights that overcoming immunotherapy resistance requires more than targeting a single pathway," said co-senior author Robert M. Samstein, MD, PhD, a physician-scientist at the Icahn School of Medicine who is Associate Professor of Radiation Oncology, and Immunology and Immunotherapy, with a laboratory in the Precision Immunology Institute. "By addressing both T cell dysfunction and the suppressive tumor environment, we can begin to design more effective combination strategies that have the potential to benefit a much broader group of patients."

According to the study, the combination therapy achieved up to 100 percent tumor clearance in models of mismatch repair-deficient colorectal cancer, and more than 70 percent clearance in mismatch repair-proficient tumors, which are typically resistant to immunotherapy.

 "This approach effectively reprograms the tumor microenvironment," said first author Guillaume Mestrallet, PhD, a postdoctoral fellow in the Bhardwaj Lab at Mount Sinai. "By simultaneously reinvigorating T cells and targeting suppressive macrophages, we were able to restore immune coordination and generate powerful anti-tumor responses."

Importantly, the study also demonstrated the development of immune memory, suggesting the potential for long-lasting protection against cancer recurrence. The findings have significant implications for the future of cancer treatment, supporting the development of rational combination immunotherapies that go beyond single-agent approaches.

The research was conducted in collaboration with investigators at the University of California- San Francisco, and supported by Mount Sinai institutional funding and grants, including a National Institutes of Health training award.