Multifaceted functions oftissue-resident memory T cells in tumorigenesis and cancer immunotherapy

Sep 23, 2026

Uploaded by Jacob

Tissue-resident memory T (TRM) cells provide immediate protection against previously encountered pathogens in non-lymphoid tissues and contribute to antitumor immunity, including enhanced survival and tumor growth inhibition across multiple cancer types. Recent findings also indicate paradoxical behavior: under certain conditions TRM cells may promote tumor progression and worsen outcomes during antitumor immune responses. This review analyzes the dual roles of TRM cells across tumor contexts and discusses how TRM-cell biology can guide future cancer immunotherapy strategies while limiting deleterious effects.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages14

Reading Time35 min

AccessFree to download

Introduction

General features of tumor-infiltrating TRM cells

Cancer Immunology, Immunotherapy (2025) 74:184 [https://doi.org/10.1007/s00262-025-04035-x](https://doi.org/10.1007/s00262-025-04035-x) Multifaceted functions oftissue‑resident memory T cells in tumorigenesis and cancer immunotherapy Eun Sang Seo1 · Sung‑Kyu Lee1 · Young Min Son1 Received: 2 December 2024 / Accepted: 24 March 2025 / Published online: 26 April 2025 © The Author(s) 2025 Abstract Tissue-resident memory T (TRM) cells are well reported as a strong protective first line of defense against foreign antigens in non-lymphoid tissues. Moreover, TRM cells have demonstrated critical protective roles in antitumor immunity, contributing to enhanced survival and tumor growth inhibition across various cancer types. However, surprisingly, recent studies suggest that TRM cells can exhibit paradoxical effects, potentially promoting tumor progression under certain conditions and leading to adverse outcomes during antitumor immune responses. Understanding the complexities of TRM cell functions will enable us to harness their potential in advancing cancer immunotherapy more effectively. Therefore, this review comprehensively investigates the dual roles of TRM cells in different tumor contexts, highlighting their protective functions in combating cancers and their unfavorable potential to exacerbate tumor development. Additionally, we explore the implications of TRM cell behaviors for future cancer treatment strategies, emphasizing the need for further research to optimize the therapeutic exploitation of TRM cells while mitigating their deleterious effects. Keywords Tumor-infiltrating lymphocytes (TILs) · Tissue-resident memory T (TRM) cells · Tumorigenesis · Cancer immunotherapy · CD103+ lymphocytes Introduction Tissue-resident memory T (TRM) cells represent a specialized subset of memory T (TMEM) cells that remain permanently localized within peripheral non-lymphoid tissues (NLTs) . These cells are strategically positioned to provide an immediate and robust immune response upon re-exposure to previously encountered pathogens [1–4] . Thus, TRM cells are present in various NLTs, including the lungs [5, 6], skin [7, 8], brain [9, 10], gut [11, 12], and other NLTs [13, 14] . TRM cell development is initiated when naive T (TN) cells differentiate into effector T cells upon activation by antigenpresenting cells (APCs) exhibiting antigenic fragments. The activated effector T cells subsequently migrate from secondary lymphoid organs, including lymph nodes and spleen, to the inflamed site, where certain cell types undergo further differentiation into TRM cells [15, 16] . The TRM cells remain in the NLTs due to the decreased expression of the * Young Min Son [Son0177@cau.ac.kr](Son0177@cau.ac.kr) 1 Department of Systems Biotechnology, Chung-Ang University, Anseong 17546, Republic of Korea cell-surface molecules such as sphingosine-1-phosphate receptor 1 (S1PR1), CC-chemokine receptor 7 (CCR7), and L-selectin (CD62L), which are typically involved in T cell migration from NLTs [17–19] . Furthermore, the TRM cells exhibit elevated tissue residency molecule expressions, such as CD69, CD103, and CD49a [20–22] . CD69 mainly parks TRM cells in the tissue by interfering with S1PR1 [21–23], and CD103 facilitates the anchoring of TRM cells to epithelial cells by binding to E-cadherin [21, 22] . CD49a interacts with collagen IV, which promotes the adhesion of TRM cells to the extracellular matrix (ECM) [22] . TRM cells are not only responsible for immune protective responses in NLTs throughout the body, including the gut, skin, respiratory system, and central nervous system [16, 24–26], but they also play a significant role in the detection and elimination of cancer cells. For instance, cytotoxic CD8+ TRM cells are known to detect tumor cells; meanwhile, tumor-infiltrating lymphocytes (TILs) have been found to exhibit significant tissue-resident memory properties, suggesting that TILs predominantly comprise TRM cells [21, 27]

FAQs

What are tissue-resident memory (TRM) cells and where are they found?

TRM cells are a specialized memory T-cell subset permanently localized in peripheral non-lymphoid tissues such as the lungs, skin, brain, and gut. They provide rapid responses upon re-exposure to previously encountered pathogens.

How do TRM cells develop and maintain tissue residency?

Naive T cells differentiate into effector T cells after activation by antigen-presenting cells and then migrate to inflamed tissues, where further differentiation generates TRM cells. TRM residency is maintained by decreased migration-related receptors (e.g., S1PR1, CCR7, CD62L) and increased residency molecules such as CD69 and CD103.

Why can TRM cells have paradoxical effects in cancer?

While TRM cells can support antitumor immunity, recent studies suggest that excessive or dysregulated TRM activity may promote tumor progression and lead to adverse outcomes. Tumor-infiltrating TRM cells may also contribute to immune-related adverse events during immune checkpoint inhibitor therapy.

Sep 23, 2026

Uploaded by Jacob