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REVIEW article

Front. Immunol.

Sec. Cancer Immunity and Immunotherapy

Volume 16 - 2025 | doi: 10.3389/fimmu.2025.1583044

This article is part of the Research Topic Mechanisms and Challenges in Cancer Immunotherapy Resistance: Bridging Extrinsic and Intrinsic Factors View all 3 articles

Mechanistic Insights into Resistance Mechanisms to T Cell Engagers

Provisionally accepted
  • 1 Roche Innovation Center Zurich, Schlieren, Switzerland
  • 2 Curie.Bio, Boston, United States
  • 3 Roche Pharma Research and Early Development, Roche Innovation Center, Basel, Switzerland

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

    T cell engagers (TCEs) represent a groundbreaking advancement in the treatment of B and plasma cell malignancies and are emerging as a promising therapeutic approach for the treatment of solid tumors. These molecules harness T cells to bind to and eliminate cancer cells, effectively bypassing the need for antigen-specific T cell recognition. Despite their established clinical efficacy, a subset of patients is either refractory to TCE treatment (e.g. primary resistance) or develops resistance during the course of TCE therapy (e.g. acquired or treatment-induced resistance).In this review we comprehensively describe the resistance mechanisms to TCEs, occurring in both preclinical models and clinical trials with a particular emphasis on cellular and molecular pathways underlying the resistance process. We classify these mechanisms into tumor intrinsic and tumor extrinsic ones. Tumor intrinsic mechanisms encompass changes within tumor cells that impact the T cell-mediated cytotoxicity, including tumor antigen loss, the expression of immune checkpoint inhibitory ligands and intracellular pathways that render tumor cells resistant to killing. Tumor extrinsic mechanisms involve factors external to tumor cells, including the presence of an immunosuppressive tumor microenvironment (TME) and reduced T cell functionality. We further propose actionable strategies to overcome resistance offering potential avenues for enhancing TCE efficacy in the clinic.

    Keywords: Resistance mechanism, T cell engager, Intrinsic mechanism, tumor microenevironment, T cell function

    Received: 25 Feb 2025; Accepted: 31 Mar 2025.

    Copyright: © 2025 Cao, Leclercq-Cohen, Klein, Sorrentino and Bacac. 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: Marina Bacac, Roche Innovation Center Zurich, Schlieren, Switzerland

    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.

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