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  • Review Article
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Biological and clinical significance of tumour-infiltrating lymphocytes in the era of immunotherapy: a multidimensional approach

Nature Reviews Clinical Oncology volume 22, pages 163–181 (2025)Cite this article

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Abstract

Immune-checkpoint inhibitors (ICIs) have improved clinical outcomes across several solid tumour types. Prominent efforts have focused on understanding the anticancer mechanisms of these agents, identifying biomarkers of response and uncovering resistance mechanisms to develop new immunotherapeutic approaches. This research has underscored the crucial roles of the tumour microenvironment and, particularly, tumour-infiltrating lymphocytes (TILs) in immune-mediated tumour elimination. Numerous studies have evaluated the prognostic and predictive value of TILs and the mechanisms that govern T cell dysfunction, fuelled by technical developments in single-cell transcriptomics, proteomics, high-dimensional spatial platforms and advanced computational models. However, questions remain regarding the definition of TILs, optimal strategies to study them, specific roles of different TIL subpopulations and their clinical implications in different treatment contexts. Additionally, most studies have focused on the abundance of major TIL subpopulations but have not developed standardized quantification strategies or analysed other crucial aspects such as their functional profile, spatial distribution and/or arrangement, tumour antigen-reactivity, clonal diversity and heterogeneity. In this Review, we discuss a conceptual framework for the systematic study of TILs and summarize the evidence regarding their biological properties and biomarker potential for ICI therapy. We also highlight opportunities, challenges and strategies to support future developments in this field.

Key points

  • A clear and widely accepted definition of tumour-infiltrating lymphocytes (TILs) has not yet been established and TILs are not systematically used as biomarkers in current oncology practice.

  • TILs comprise a spectrum of numerous lymphocyte subsets with dissimilar abundance, functional states, marker profiles, antigen specificity, clonal expansion, spatial distribution and dynamics; resolving the relative contribution of different TIL features and/or integration of these diverse parameters is key to exploiting their clinical value.

  • Cytotoxic T cells mediate tumour elimination induced by immune-checkpoint inhibitors (ICIs), the role of other T cell subsets and B cells in the recognition and eradication of malignant cells is less clear.

  • The abundance of intratumoural T cells and/or B cells (typically forming tertiary lymphoid structures) is positively associated with prognosis across most solid tumour types and might be predictive of sensitivity to ICIs and other immunotherapies.

  • The functional (or dysfunctional) profile of TILs determines their capacity to eliminate cancer cells and has prominent biomarker potential. Spatial features of TILs such as their location within the tumour microenvironment, distribution and/or clustering, infiltration patterns and topographical heterogeneity can also affect their biological responses, association with immunotherapy outcomes and might inform therapeutic avenues.

  • The application of modern technologies such as multiparametric single-cell molecular analysis, spatially resolved immunoprofiling tools and deep learning or other artificial intelligence platforms is redefining our understanding of the composition and analysis of TILs.

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Fig. 1: Biological properties of TILs and their role in immunotherapy.
Fig. 2: TILs, TLS and spatial compartments in cancer.
Fig. 3: Associations of TILs with ICI treatment outcomes in patients with solid tumours.
Fig. 4: Spatial heterogeneity of TIL infiltration patterns.

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Acknowledgements

The work of the authors is supported by NIH grants R37CA245154, R01CA262377, R01CA216579 and P50CA196530.

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Authors and Affiliations

  1. Department of Pathology and Yale Cancer Center, Yale University School of Medicine, New Haven, CT, USA

    Miguel Lopez de Rodas, Maria Villalba-Esparza, David L. Rimm & Kurt A. Schalper

  2. Department of Pathology, Cancer Center Clinica Universidad de Navarra, Pamplona, Navarra, Spain

    Miguel Lopez de Rodas

  3. Department of Immunology and Immunotherapy, Centro de Investigación Médica Aplicada and Clínica Universidad de Navarra, Pamplona, Navarra, Spain

    Miguel F. Sanmamed

  4. Department of Immunobiology, Yale University School of Medicine, New Haven, CT, USA

    Lieping Chen

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M.L.d.R., M.V.-E. and K.A.S. researched data for the article and wrote the manuscript. All authors contributed substantially to discussion of the content and reviewed and/or edited the manuscript before submission.

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M.F.S. had received fees for consultancy from Bristol Myers Squibb, MSD, Numab and Roche; and his laboratory has received funding from Bristol Myers Squibb and Roche. L.C. has been a consultant for NextCure, OncoC4, Tcelltech and Zai Lab; is a scientific founder of DynamiCure, NextCure, Normunity and Tcelltech; and his laboratory has received funding from DynamiCure, NextCure and Normunity. D.L.R. has served as an adviser for Agendia, Amgen, AstraZeneca, Bristol Myers Squibb, Cell Signalling Technology, Cepheid, Danaher, Daiichi Sankyo, Genoptix/Novartis, GSK, Halda Biotherapeutics, Incendia, Konica Minolta, Merck, NanoString, PAIGE.AI, Perkin Elmer, Roche, Sanofi and Ventana; and his laboratory has received funding from Amgen, Cepheid, Navigate Biopharma, NextCure, Leica and Konica Minolta. K.A.S. has served as a consultant, adviser or speaker for Agenus, AstraZeneca, Bristol Myers Squibb, Clinica Alemana Santiago, CSRlife, Dynamicure, EMD Serono, Forefront Collaborative, Genmab, Indaptus, Merck, Merus, Moderna, Molecular Templates, OnCusp, Parthenon Therapeutics, PeerView, Physicians Education Resource, Roche, Sanofi, Shattuck Labs, Takeda and Torque/Repertoire Therapeutics; and his laboratory has received research funding from Akoya Biosciences, AstraZeneca, Boehringer-Ingelheim, Bristol Myers Squibb, Eli Lilly, Merck, NextPoint Therapeutics, Ribon Therapeutics, Roche, Surface Oncology, Takeda and Tesaro/GSK. M.L.d.R. and M.V.-E. declare no competing interests.

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Lopez de Rodas, M., Villalba-Esparza, M., Sanmamed, M.F. et al. Biological and clinical significance of tumour-infiltrating lymphocytes in the era of immunotherapy: a multidimensional approach. Nat Rev Clin Oncol 22, 163–181 (2025). https://doi.org/10.1038/s41571-024-00984-x

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