REVIEW article

Front. Immunol.

Sec. Cancer Immunity and Immunotherapy

Volume 16 - 2025 | doi: 10.3389/fimmu.2025.1614228

This article is part of the Research TopicUnderstanding the Interplay Between Tumor Immune Microenvironment and Neoantigens for Improved ImmunotherapyView all 4 articles

Breaking Down Physical Barriers: Strategies to Improve Lymphocyte Infiltration for Effective Neoantigen-Based Therapies

Provisionally accepted
  • 1Department of Gastroenterology, The Second Hospital & Clinical Medical School, Lanzhou University, Lanzhou, China
  • 2Department of Gastroenterology, The Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China
  • 3The first Clinical Medical College of Lanzhou University, Lanzhou, China
  • 4Sichuan University, Chengdu, China

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

The cancer genomic instability drives the generation of neoantigens, making them ideal targets for immunotherapy. Neoantigen-specific tumor-infiltrating lymphocytes achieve precise tumor cell killing by recognizing neoantigens on the tumor surface, but their efficacy is limited by complex physical barriers within the tumor microenvironment. These barriers not only directly impede TIL migration and infiltration but also synergize with immunosuppressive signals to weaken antitumor immune responses. The tumor extracellular matrix forms a dense fibrous network due to enhanced collagen crosslinking, pathological hyaluronic acid deposition, and increased stiffness, hindering TIL mobility. Aberrant tumor vasculature, characterized by hyperpermeability and elevated interstitial fluid pressure, collaborates with pro-fibrotic factors, such as VEGF, TGF-β secreted by cancerassociated fibroblasts and regulatory T cells to create mechanical compression barriers. This review systematically explores the composition, molecular mechanisms, and therapeutic strategies targeting these physical barriers, providing novel insights for neoantigen-based therapies. Future efforts should integrate biomechanical interventions with immunotherapy, elucidate the interplay between mechanical signaling and immunometabolism, and optimize multi-target combinatorial approaches to enhance the clinical translation potential of neoantigen therapies.

Keywords: neoantigen, Tumor-infiltrating lymphocytes, Extracellular Matrix, interstitial fluid pressure, cancer-associated fibroblasts

Received: 18 Apr 2025; Accepted: 28 May 2025.

Copyright: © 2025 Chen, Li, Zhang, Kang, Zhang, Zhang, Sangmao, Zhu and Zhang. 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:
Yajuan Zhu, Sichuan University, Chengdu, China
Dekui Zhang, Department of Gastroenterology, The Second Hospital & Clinical Medical School, Lanzhou University, Lanzhou, China

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