Researchers at the Icahn School of Medicine at Mount Sinai and the Mount Sinai Tisch Cancer Center have identified a promising new approach to overcoming immunotherapy resistance in colorectal cancer (CRC)—one of the most common and lethal cancers worldwide. In a recent study published in the May 5, 2026, online edition of Cell Reports Medicine (10.1016/j.xcrm.2026.102786)[1], the team demonstrated that restoring coordinated communication between key immune cell types can dramatically enhance anti-tumor immune responses and lead to durable tumor clearance.[1]
Immunotherapy, particularly immune checkpoint blockade (ICB) targeting PD-1, has transformed cancer treatment, but many patients with CRC—especially those with so-called mismatch repair-proficient (MMRp) tumors—fail to respond. Even among mismatch repair-deficient (MMRd) tumors*, which are typically more immunogenic, up to 50% of advanced cases exhibit resistance to anti-PD-1 therapy. The mechanisms underlying this resistance are complex and not fully understood.[2]
Studies have shown that up to 30% of patients diagnosed with colorectal, endometrial, and gastric cancers have a deficiency in mismatch repair (MMR) protein expression. which is understood to result from either germline or epigenetic inactivation. Patients with Lynch Syndrome, one of the most prevalent hereditary cancer syndromes in humans, account for some 3% of unselected patients with colorectal or endometrial cancer and 10%-15% of those with MMRd, who inherit an inactive MMR allele have an up to 80% risk for developing a MMRd cancer. [3]
Study Findings
Using advanced preclinical mouse models and single-cell analyses, the Mount Sinai-led team uncovered that effective anti-tumor immunity in CRC depends not only on activating T-cells, but also on restoring communication and cooperation between T-cells and specialized myeloid cells, particularly macrophages. The researchers found that exhausted T-cells and an abundance of immunosuppressive TREM2+ macrophages characterize immunotherapy-resistant tumors.[1]
The investigators then tested a novel combination therapy that simultaneously targeted multiple T-cell checkpoints (PD-1, CTLA-4, LAG3) along with TREM2, a marker of immunosuppressive macrophages. This multi-pronged approach resulted in striking tumor clearance rates—up to 100% in mismatch repair-deficient models and over 70% in mismatch repair-proficient models that are otherwise resistant to immunotherapy.
Mechanistic Insights
The study revealed that successful anti-tumor responses are orchestrated by close interactions between MHC+ C1Q+ CXCL9+ macrophages and activated TCF+ CD8+ and CD4+ T-cells within the tumor microenvironment. By blocking TREM2, LAG3, CTLA-4, and PD-1, the combination therapy reinvigorated T-cells, reduced immunosuppressive myeloid infiltration, and restored immune cell communication, leading to robust anti-tumor immunity.
Importantly, treated mice developed immune memory, providing protection against tumor recurrence and suggesting the possibility of durable, long-term benefit.
Clinical Implications
These findings have significant implications for the future of immunotherapy in CRC.
“Our results show that overcoming immunotherapy resistance requires more than activating T-cells—it demands reprogramming the tumor microenvironment to support immune cell cooperation,” said co-senior author Nina Bhardwaj, MD, PhD.
“By rationally combining immune checkpoint inhibitors and myeloid cell-targeting agents, we can dramatically expand the group of patients who may benefit from immunotherapy,” Bhardwaj added.
The approach was found effective in both mismatch repair-deficient and proficient tumors, broadening its potential impact. Machine learning models applied to single-cell data accurately predicted patient responses to immunotherapy based on immune cell profiles, offering a path toward more personalized treatment strategies.
Next Steps and Future Directions
While these results are compelling, the researchers noted that further validation in clinical trials will be needed to confirm safety and efficacy in patients. The study supports the development of rational combination immunotherapies tailored to individual tumor immune landscapes, with the goal of overcoming resistance and achieving durable responses in both MMRd and MMRp colorectal cancer.
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Note:* Mismatch repair-deficient (dMMR) describes cells that have a dysfunctional system for correcting errors that naturally occur when DNA is copied (replicated). Because these “spell-check” genes are not functioning, cells accumulate many mutations, a state known as high microsatellite instability (MSI-H), which can lead to cancer development.
The research was conducted in collaboration with the University of California–San Francisco and supported by institutional and NIH funding. Click here for a full study and contributor list.
Reference
[1] Mestrallet G, Brown M, Vaninov N, Cho NW, Velazquez L, Ananthanarayanan A, Spitzer M, Vabret N, Bozkus CC, Samstein RM, Bhardwaj N. Reprogramming T cell-myeloid crosstalk overcomes immune resistance in colorectal cancer Cell Reports Medicine. 2026;10.1016/j.xcrm.2026.102786.
[2] Le DT, Durham JN, Smith KN, Wang H, Bartlett BR, Aulakh LK, Lu S, Kemberling H, Wilt C, Luber BS, Wong F, Azad NS, Rucki AA, Laheru D, Donehower R, Zaheer A, Fisher GA, Crocenzi TS, Lee JJ, Greten TF, Duffy AG, Ciombor KK, Eyring AD, Lam BH, Joe A, Kang SP, Holdhoff M, Danilova L, Cope L, Meyer C, Zhou S, Goldberg RM, Armstrong DK, Bever KM, Fader AN, Taube J, Housseau F, Spetzler D, Xiao N, Pardoll DM, Papadopoulos N, Kinzler KW, Eshleman JR, Vogelstein B, Anders RA, Diaz LA Jr. Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade. Science. 2017 Jul 28;357(6349):409-413. doi: 10.1126/science.aan6733. Epub 2017 Jun 8. PMID: 28596308; PMCID: PMC5576142.
[3] Mestrallet G, Brown M, Bozkus CC, Bhardwaj N. Immune escape and resistance to immunotherapy in mismatch repair deficient tumors. Front Immunol. 2023 Jul 10;14:1210164. doi: 10.3389/fimmu.2023.1210164. PMID: 37492581; PMCID: PMC10363668.
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DOI
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