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Establishment of a Co-culture System of Patient-Derived Colorectal Tumor Organoids and Tumor-Infiltrating Lymphocytes (TILs)
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Decoding Immunotherapy Response in Colorectal Cancer: Translational Insights Beyond MSI
Chiara Cataldi1, Beliz Bahar Karaoğlan2, Elena Liotta3
1Department of Molecular Medicine, Sapienza University of Rome, 00161 Rome, Italy.
Cancers
|March 14, 2026
Summary
Immune checkpoint inhibitors (ICIs) show promise in colorectal cancer (CRC), but resistance is common. New biomarkers beyond mismatch repair deficiency are needed to predict response and guide combination therapies for better patient selection.
Area of Science:
- Oncology
- Immunology
- Genetics
Background:
- Immune checkpoint inhibitors (ICIs) offer transformative treatment for various cancers, including colorectal cancer (CRC).
- Current ICI efficacy in CRC is primarily restricted to mismatch repair-deficient (dMMR) or microsatellite instability-high (MSI-H) subtypes.
- Primary and acquired resistance to ICIs limit clinical benefit, necessitating further biomarker discovery.
Purpose of the Study:
- To review established and emerging biomarkers predicting response and resistance to ICIs in colorectal cancer.
- To synthesize evidence from clinical trials, translational studies, and reviews on immunotherapy biomarkers in CRC.
- To inform patient selection and the development of rational combination strategies for CRC treatment.
Main Methods:
- A narrative review approach was employed.
- Literature search conducted for emerging biomarkers of immunotherapy response in colorectal cancer.
- Synthesis of relevant clinical trials, translational studies, and reviews.
Main Results:
- Deficient mismatch repair/high microsatellite instability (dMMR/MSI-H) remains the most reliable predictive biomarker.
- High tumor mutational burden, POLE/POLD mutations, and tumor microenvironment features are associated with ICI response.
- Emerging biomarkers include molecular alterations, antigen presentation machinery, PD-L1 signaling, microbiome, and circulating tumor DNA kinetics, showing potential for MSI-H and MSS CRC.
Conclusions:
- Immunotherapy response in CRC is multifactorial, involving tumor-intrinsic, immune, microenvironmental, and systemic factors.
- Integrating multiple biomarkers may enhance patient stratification and guide therapeutic strategies.
- Prospective validation and standardized assessment are crucial for clinical translation of biomarkers.
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