Journal of Hepatology and Gastrointestinal disorders
Open Access

The Evolving Landscape of Immunotherapy in Gastrointestinal Malignancies

Jonathan E. Clarke^{* *}Correspondence: Jonathan E. Clarke, Department of Oncology and Translational Immunotherapy, University of Toronto, Princess Margaret Cancer Centre, Toronto, Ontario, Canada, Email:

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Description

The treatment landscape of GastroIntestinal (GI) cancers has undergone a profound transformation in the past decade. Once dominated by cytotoxic chemotherapy and limited surgical options, GI oncology now stands on the threshold of a new era one defined by the rise of immunotherapy. Immune checkpoint inhibitors, cancer vaccines and adoptive cell therapies are beginning to redefine how clinicians approach even the most treatment-resistant malignancies, including gastric, colorectal, hepatobiliary and pancreatic cancers. While immunotherapy has revolutionized cancers like melanoma and non-small cell lung cancer, its application in GI malignancies has been more nuanced. The GI tract is an immunologically complex environment, heavily influenced by microbial antigens, chronic inflammation and immune tolerance mechanisms. These factors pose unique challenges to immune activation but also present opportunities to harness the immune system in sophisticated, tissue-specific ways.

Checkpoint inhibition, particularly PD-1 and PD-L1 blockade, has shown meaningful success in select GI tumor subtypes. Microsatellite Instability-High (MSI-H) or Mismatch Repair-deficient (dMMR) colorectal cancers represent a key success story. These tumors are hypermutated and express high levels of neoantigens, making them susceptible to immune recognition. Pembrolizumab and nivolumab are now standard of care for this subset, offering durable responses and in some cases, long-term remission. This has underscored the importance of molecular profiling in GI oncology, as a patient's biomarker status increasingly dictates therapeutic strategy. However, most GI tumors are MicroSatellite Stable (MSS), characterized by a "cold" immune microenvironment with minimal T-cell infiltration. This has limited the efficacy of single-agent checkpoint blockade. In these settings, combination strategies have taken center stage. Trials are now exploring the synergy between checkpoint inhibitors and chemotherapy, anti-angiogenic agents, radiation and even gut microbiota modulation. For example, the addition of atezolizumab to bevacizumab in unresectable hepatocellular carcinoma has significantly extended survival, representing a landmark shift in first-line therapy.

Gastric and esophageal cancers have also seen meaningful progress. The CheckMate 649 trial demonstrated a survival benefit with nivolumab plus chemotherapy in advanced gastric/GEJ cancers, especially in PD-L1-positive patients. This finding has reshaped treatment protocols in high-income countries, where immunotherapy access is widespread. Nonetheless, patient selection remains critical, as not all PD-L1-positive tumors respond equally and predictive biomarkers beyond PD-L1 expression are urgently needed. Emerging research is focused on Tumor Mutational Burden (TMB), immune gene signatures and gut microbiome composition to better predict response. Additionally, novel targets beyond PD-1 and CTLA-4, such as LAG-3, TIM-3 and TIGIT, are being explored to overcome immune resistance in refractory cases. These next-generation checkpoint inhibitors may enable deeper and broader immune activation when used alone or in combination.

In pancreatic cancer, arguably the most immunotherapy-resistant GI malignancy, progress has been slow but not stagnant. The immunosuppressive stroma and lack of immune cell infiltration pose major barriers. However, preclinical and early-phase trials are investigating stromal modulation, oncolytic viruses and vaccine approaches as a way to "prime" tumors for immunotherapy. Personalized neoantigen vaccines, designed using tumor-specific mutations, have shown promise in generating T-cell responses, although clinical benefits remain under investigation. Adoptive cell therapies, including CAR-T cells and Tumor-Infiltrating Lymphocyte (TIL) therapy, are also being tailored for GI cancers. While logistical and biological challenges persist such as antigen heterogeneity and off-target toxicity innovations in gene editing and cell engineering are steadily improving safety and efficacy profiles. High-income centers with advanced cell therapy infrastructure are pioneering these approaches, laying the groundwork for broader adoption.

Despite these encouraging advances, challenges remain. Immune-related adverse events, ranging from mild rash to severe colitis and hepatitis, require vigilant monitoring and multidisciplinary management. Cost and access also remain barriers, especially in middle-income settings, although high-income countries are increasingly integrating these therapies into national cancer programs and clinical pathways. From a health systems perspective, the shift toward immunotherapy demands a new framework for care. Oncologists must now be equipped with immunology expertise, biomarker interpretation skills and familiarity with combination regimens. Multidisciplinary collaboration with radiologists, pathologists, microbiome scientists and immunologists is essential for maximizing treatment potential.

Conclusion

The evolving role of immunotherapy in gastrointestinal malignancies reflects a paradigm shift from one-size-fits-all treatment to biologically-driven, immune-based precision oncology. Although progress has been uneven across tumor types, the trajectory is clearly forward. In high-income countries, where research capacity, biomarker testing and drug access are robust, the integration of immunotherapy is already reshaping clinical outcomes. As we move deeper into the era of immunooncology, ongoing research must focus on overcoming resistance, refining predictive tools and ensuring equitable access to novel therapies. The immune system, once considered a passive observer in GI cancer, is now an active therapeutic ally and its full potential is only beginning to be realized.