Mount Sinai Study Identifies New Strategy to Overcome Immunotherapy Resistance in Colorectal Cancer

Mount Sinai Study Identifies New Strategy to Overcome Immunotherapy Resistance in Colorectal Cancer

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," said co-senior author Nina Bhardwaj, MD, PhD, 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. "You also need to restore the communication between immune cells so they can work together effectively against the tumor."

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.

Full study and list of contributors: https://www.cell.com/cell-reports-medicine/fulltext/S2666-3791(26)00203-X

About the Icahn School of Medicine at Mount Sinai

The Icahn School of Medicine at Mount Sinai is internationally renowned for its outstanding research, educational, and clinical care programs. It is the sole academic partner for the seven member hospitals* of the Mount Sinai Health System, one of the largest academic health systems in the United States, providing care to New York City's large and diverse patient population.

The Icahn School of Medicine at Mount Sinai offers highly competitive MD, PhD, MD-PhD, and master's degree programs, with enrollment of more than 1,200 students. It has the largest graduate medical education program in the country, with more than 2,700 clinical residents and fellows training throughout the Health System. The Graduate School of Biomedical Sciences offers 13 degree-granting programs, conducts innovative basic and translational research, and trains more than 470 postdoctoral research fellows.

Ranked 11th nationwide in National Institutes of Health (NIH) funding, the Icahn School of Medicine at Mount Sinai is among the 90th percentile of U.S. private medical schools in Sponsored Programs Direct Expenditures per Principal Investigator, according to the Association of American Medical Colleges. More than 6,900 scientists, educators, and clinicians work within and across dozens of academic departments and multidisciplinary institutes with an emphasis on translational research and therapeutics. Through Mount Sinai Innovation Partners (MSIP), the Health System facilitates the real-world application and commercialization of medical breakthroughs made at Mount Sinai.

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* Mount Sinai Health System member hospitals: The Mount Sinai Hospital; Mount Sinai Brooklyn; Mount Sinai Morningside; Mount Sinai Queens; Mount Sinai South Nassau; Mount Sinai West; and New York Eye and Ear Infirmary of Mount Sinai.

About the Mount Sinai Health System

Mount Sinai Health System is one of the largest academic medical systems in the New York metro area, with more than 47,000 employees working across seven hospitals, more than 400 outpatient practices, more than 600 research and clinical labs, a school of nursing, and leading schools of medicine and graduate education. Mount Sinai advances health for all people, everywhere, by taking on the most complex health care challenges of our time-discovering and applying new scientific learning and knowledge; developing safer, more effective treatments; educating the next generation of medical leaders and innovators; and supporting local communities by delivering high-quality care to all who need it.

Through the integration of its hospitals, labs, and schools, Mount Sinai offers comprehensive health care from conception through geriatrics, leveraging innovative approaches such as artificial intelligence and informatics while keeping patients' medical and emotional needs at the center of all treatment. The Health System includes more than 6,400 primary and specialty care physicians and 10 free-standing joint-venture centers throughout the five boroughs of New York City, Westchester, Long Island, and Florida. Hospitals within the System are consistently ranked by Newsweek's® "The World's Best Smart Hospitals," "Best in State Hospitals," "World's Best Hospitals," and "Best Specialty Hospitals" and by U.S. News & World Report's® "Best Hospitals" and "Best Children's Hospitals." The Mount Sinai Hospital is on the U.S. News & World Report® "Best Hospitals" Honor Roll for 2025-2026.

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