Efficient antigen processing and presentation mechanisms are fundamental for immune surveillance, enabling effective recognition and elimination of cancerous cells. Within gastro-intestinal cancers, disturbances in antigen-presenting processes—encompassing antigen uptake, processing, loading onto MHC molecules, presentation to T-cells, as well as associated protein quality control (PQC) mechanisms such as the ubiquitin-proteasome system, autophagy, and the unfolded protein response—significantly contribute to tumor immune evasion and disease progression. Recent research underscores the critical connections between aberrations in antigen presentation and PQC pathways, highlighting them as potential therapeutic targets to stimulate and restore anti-tumor immunity. Despite these advances, comprehensive understanding of how disruptions in these interconnected pathways facilitate tumor immunosuppression remains incomplete, limiting their clinical exploitation.

This Research Topic aims to elucidate the complex molecular interactions linking antigen presentation with protein quality control pathways in gastro-intestinal cancers, and to highlight innovation in therapeutically targeting such pathways to enhance anti-tumor immune responses. We aim to better characterize how disruptions in the antigen processing machinery and PQC contribute to immune avoidance strategies, evaluate emerging therapeutic interventions (e.g., small molecule modulators, targeted antibodies, or gene-engineering methods), and explore opportunities for integrating these strategies with existing immune-based therapies. Furthermore, this topic aspires to identify novel biomarkers and collect robust preclinical and clinical evidence that supports the translation of these insights into improved patient outcomes.

We invite submissions addressing, but not limited to, the following themes:
• Antigen Presentation Mechanisms: Investigating molecular drivers of impaired antigen capture, processing, or presentation in gastro-intestinal cancers, and their impact on tumor immunogenicity.
• Protein Quality Control Interactions: Exploring how dysregulated PQC pathways influence antigen presentation and subsequent immune responses within the tumor microenvironment.
• Therapeutic Strategies: Development and assessment of novel agents or methods targeting antigen-presenting and PQC pathways to improve cancer immunotherapy efficacy.
• Immunological Implications: Evaluating how manipulation of PQC and antigen presentation modulates tumor-infiltrating immune cell functions and enhances anti-tumor immunity.
• Clinical Translation and Biomarkers: Identifying biomarkers indicative of pathway deregulation and therapeutic response; integrating such approaches into existing therapeutic regimens.
• Preclinical and Clinical Validation: Reports on validated models (in vitro/in vivo) or clinical studies addressing the therapeutic potential of targeting antigen presentation and PQC mechanisms.

We welcome original research articles, comprehensive reviews, and thought-provoking opinion submissions contributing significant insights into these intertwined cellular processes, their role in tumors' immune escape mechanisms, and their potential as targets for cancer therapy.

Please note: manuscripts consisting solely of bioinformatics, computational analysis, or predictions of public databases which are not accompanied by validation (independent clinical or patient cohort, or biological validation in vitro or in vivo, which are not based on public databases) are not suitable for publication in this journal.

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Targeting Antigen Presentation and Protein Quality Control Pathways to Enhance Tumor Immunity in Gastro-Intestinal Cancers