article · Cancers
Immune checkpoint inhibitors have transformed care for specific gastrointestinal tumours, particularly those with high microsatellite instability or mismatch repair deficiencies. Despite these successes, the majority of gastrointestinal cancers fail to respond to current standard PD-1 and PD-L1 immunotherapies. This resistance stems from complex, highly suppressive tumour microenvironments marked by stromal exclusion, myeloid-driven suppression, defective antigen presentation, and adaptive immune resistance. Alternative inhibitory checkpoint pathways, including LAG-3, TIGIT, TIM-3, and VISTA, actively drive ongoing T-cell dysfunction. Overcoming these hurdles requires next-generation checkpoint inhibitors and multimodal combination strategies that unite novel inhibitors with chemotherapy, anti-angiogenic treatments, radiotherapy, bispecific antibodies, or microenvironment modulators. Additionally, improving durable clinical outcomes depends heavily on advancing patient stratification through biomarkers such as circulating tumour DNA, spatial immune profiling, and multi-omics approaches.
Most gastrointestinal cancers do not respond to standard immunotherapies, leaving many patients with limited treatment options. Clarifying the biological mechanisms behind treatment resistance and identifying alternative immune checkpoints helps guide the design of more effective therapies. Furthermore, refining biomarker tools enables clinicians to match patients with the right targeted combinations, improving response rates and long-term survival.
This work informs drug developers and biotechnology companies working on next-generation immune checkpoint inhibitors, bispecific antibodies, and combination oncology regimens. It also points to commercial opportunities for diagnostics developers creating circulating tumour DNA assays, spatial profiling platforms, and multi-omics stratification tools. Because the described therapies and biomarkers are currently in development or undergoing clinical evaluation, these applications range from early translational research to active clinical trials.
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Immune checkpoint inhibitors (ICIs) have significantly changed the treatment landscape of several gastrointestinal (GI) malignancies, particularly microsatellite instability-high (MSI-H) and mismatch repair-deficient (dMMR) tumors. However, most GI cancers remain resistant to current PD-1/PD-L1-based immunotherapy because of complex and highly suppressive tumor microenvironments characterized by immune stromal exclusion, myeloid-driven immune suppression, defective antigen presentation, and adaptive immune resistance mechanisms. Emerging evidence suggests that alternative inhibitory pathways, including lymphocyte activation gene-3 (LAG-3), T-cell immunoreceptor with immunoglobulin and ITIM domain (TIGIT), T-cell immunoglobulin and mucin-domain containing-3 (TIM-3), and V-domain Ig suppressor of T-cell activation (VISTA), contribute substantially to persistent T-cell dysfunction and resistance to checkpoint blockade. This review summarizes the immune landscape of GI malignancies and discusses the biological mechanisms underlying resistance to current ICIs. We highlight the evolving role of next-generation immune checkpoints, ongoing clinical development of novel inhibitors, and emerging combination strategies involving chemotherapy, anti-angiogenic therapy, radiation, bispecific antibodies, and tumor microenvironment modulation. In addition, we discuss current limitations in biomarker development and the growing role of circulating tumor DNA, spatial immune profiling, and multi-omics approaches in patient selection. Finally, we explore future directions aimed at improving precision immunotherapy and expanding durable responses across GI cancers.
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DOI: 10.3390/cancers18162593
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