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REVIEW article

Front. Immunol.
Sec. Cancer Immunity and Immunotherapy
Volume 15 - 2024 | doi: 10.3389/fimmu.2024.1414376

Mismatch Repair-proficient tumor footprints in the sands of immune desert: mechanistic constraints and precision platforms

Provisionally accepted
Biswanath Majumder Biswanath Majumder *Leela Maitreyi Leela Maitreyi Nishanth B. Nataraj Nishanth B. Nataraj Santanu Datta Santanu Datta
  • Bugworks Research India, Bangalore, India

The final, formatted version of the article will be published soon.

    Mismatch repair proficient (MMRp) tumors of colorectal origin are one of the prevalent yet unpredictable clinical challenges. Despite earnest efforts, optimal treatment modalities have yet to emerge for this class. The poor prognosis and limited actionability of MMRp are ascribed to a low neoantigen burden and a desert-like microenvironment. This review focuses on the critical roadblocks orchestrated by an immune evasive mechanistic milieu in the context of MMRp. The low density of effector immune cells, their weak spatiotemporal underpinnings, and the high-handedness of the IL17-TGF signaling are intertwined and present formidable challenges for the existing therapies. Microbiome niche decorated by Fusobacterium nucleatum alters the metabolic program to maintain an immunosuppressive state. We also highlight the evolving strategies to repolarize and reinvigorate this microenvironment.Reconstruction of anti-tumor chemokine signaling, rational drug combinations eliciting T cell activation, and reprograming the maladapted microbiome are exciting developments in this direction. Alternative vulnerability of other DNA damage repair pathways is gaining momentum. Integration of liquid biopsy and ex vivo functional platforms provide precision oncology insights. We illustrated the perspectives and changing landscape of MMRp-CRC.The emerging opportunities discussed in this reviewcan turn the tide in favour of fighting the treatment dilemma for this elusive cancer.

    Keywords: colorectal cancer, MMRP, Tumor immune microenvironment, Gut Microbiota, therapeutic vulnerability, predictive biomarkers, precision medicine, functional platforms

    Received: 08 Apr 2024; Accepted: 17 Jun 2024.

    Copyright: © 2024 Majumder, Maitreyi, Nataraj and Datta. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

    * Correspondence: Biswanath Majumder, Bugworks Research India, Bangalore, India

    Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.