Cancers of the gastrointestinal tract, including those of the esophagus, stomach, and colorectum, represent a leading cause of global cancer-related mortality. While immunotherapy has emerged as a transformative pillar of oncology, its application and success across these diverse malignancies have been markedly uneven. Many patients derive only limited benefit or develop resistance, highlighting an urgent need for smarter, biologically-guided treatment strategies. Published on February 20, 2026, in the journal Immunity & Inflammation , Prof. Rui-Hua Xu proposes a transformative approach to using immunotherapy for cancers of the gastrointestinal tract.
The review begins by acknowledging the established but limited role of PD-1/PD-L1 inhibitors in gastrointestinal oncology. While these drugs are standard for certain subtypes like deficient mismatch repair (dMMR) metastatic colorectal cancer (CRC), and are combined with chemotherapy for many esophageal and gastric cancers, primary and acquired resistance remains a significant hurdle for most patients. This heterogeneity stems from fundamental differences in the tumor immune microenvironment (TME).
To rationally address this diversity, the article systematically constructs a "three-strata" model to guide therapeutic development. The first stratum includes highly immunogenic tumors, such as dMMR or microsatellite instability-high (MSI-H) cancers across the gastrointestinal tract. Characterized by a high mutational burden, pre-existing T cell infiltration, and inflammatory signals, these tumors are exceptionally responsive to immune checkpoint blockade. For this group, the review advocates for a paradigm shift toward chemotherapy-free, immunotherapy-centric strategies, even exploring non-surgical, curative-intent approaches in localized disease to improve quality of life.
The second stratum encompasses tumors with intermediate sensitivity, notably many gastroesophageal adenocarcinomas and squamous cell carcinomas. These cancers possess a more complex and balanced TME, containing both effector and suppressive immune cells. Here, the combination of immunotherapy with chemotherapy has become a cornerstone of treatment, leveraging chemotherapy's ability to induce immunogenic cell death and modulate the TME. The review delves into optimizing these combinations, discussing the immunogenic potential of specific chemotherapeutic agents, such as oxaliplatin and paclitaxel, and the ongoing challenge of identifying biomarkers beyond PD-L1 expression to better select patients.
The third and most challenging stratum includes poorly immunogenic, "immune-cold" tumors, exemplified by proficient mismatch repair (pMMR) or microsatellite stable CRC. These tumors are defined by a TME dominated by exclusionary stroma, suppressive myeloid cells, and dysfunctional T cells. The review critically analyzes past failures of simple combination therapies and argues that overcoming resistance in this group will require rationally designed, higher-order combinations. These strategies must simultaneously tackle multiple barriers—such as combining immunotherapy with agents that normalize vasculature, reverse T cell exhaustion, or target liver-specific immunosuppression—as illustrated by emerging positive clinical trial data.
The authors state, " This framework moves us beyond a one-size-fits-all approach. " " By stratifying tumors based on their inherent immune phenotype, we can deploy more precise and potent strategies, from de-escalating therapy in the most responsive groups to building sophisticated combinations for the most resistant ones. "
Looking forward, the review highlights the integration of next-generation modalities, such as bispecific T-cell engagers, antibody-drug conjugates, and CAR-T cell therapy, which offer new mechanisms to overcome resistance. It also emphasizes the critical role of dynamic, multi-omics biomarker development and artificial intelligence to power the personalized application of these evolving strategies, aiming to extend the benefits of immunotherapy to a much broader patient population.
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Reference
DOI: 10.1007/s44466-026-00025-5
About Immunity & Inflammation
Immunity & Inflammation is a newly launched open-access journal co-published by the Chinese Society for Immunology and Springer Nature under the leadership of Editors-in-Chief Prof. Xuetao Cao and Prof. Jules A. Hoffmann. Immunity & Inflammation aims to publish major scientific questions and cutting-edge advances that explore groundbreaking discoveries and insights across the spectrum of immunity and inflammation, from basic science to translational and clinical research.
Website: https://link.springer.com/journal/44466
About Author s
Prof. Rui-Hua Xu from Sun Yat-sen University
Rui-Hua Xu is an Academician of the Chinese Academy of Engineering. He serves as the Director of the Sun Yat-sen University Cancer Center, including an affiliated hospital and research institute. Recognized as a Clarivate Highly Cited Researcher for two consecutive years, he has received numerous honors, including two National Science and Technology Progress Awards (Second Class), the National Award for Innovation and Excellence, the Ho Leung Ho Lee Foundation Prize, the Wu Jieping Medical Innovation Award, the Tan Jiazhen Clinical Medicine Award, and the CSCO Annual Achievement Award. His research focuses on immunotherapy for gastrointestinal cancers.
Dr. Zi-Xian Wang from Sun Yat-sen University Cancer Center
Dr. Zi-Xian Wang is an Associate Chief Physician at the Sun Yat-sen University Cancer Center. His clinical and research focus is immunotherapy for gastrointestinal cancers.
Funding information
This work was supported by the Noncommunicable Chronic Diseases-National Science and Technology Major Project (2023ZD0501600), the National Natural Science Foundation of China (82321003, 82173128, 82473362, 82203006), the Natural Science Foundation of Guangdong Province (2024A1515012980, 2025B1515020081), the Young Elite Scientists Sponsorship Program by CAST (2023QNRC001), the Cancer Innovative Research Program of Sun Yat-sen University Cancer Center (CIRP-SYSUCC-0004), and the Sun Yat-sen University Clinical Research 5010 Program (84000-31630002).
Systematic review
Not applicable
Optimizing immunotherapy for gastrointestinal tract cancers: clinical progress and perspectives
20-Feb-2026
The corresponding author, Rui-Hua Xu, reported participating on advisory boards for Astellas, MSD, AstraZeneca, Junshi, Hengrui, BeiGene, Innovent, Hutchison, Qilu, CPPC, and Keymed. The authors declare no other competing interests.