Targeting T cell exhaustion in colorectal cancer - emerging roles of LAG-3, TIM-3, and TIGIT signaling in overcoming immunotherapy resistance

Sep 22, 2026

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Exhaustion of T cells, marked by impaired function and reduced cytokine production, was first described in chronic infections and is now understood in the immunosuppressed tumor microenvironment. In colorectal cancer, exhaustion is linked to immune checkpoint pathways including PD-1, TIM-3, LAG-3, and TIGIT. While anti-PD-1 trials show limited efficacy, combining blockade of additional checkpoints with PD-1 is discussed. The review also highlights emerging exhaustion signaling concepts, including potential prognostic value and combination therapy challenges.

LanguageEnglish

CategoryResearch & Report

FormatPDF

Pages11

Reading Time28 min

AccessFree to download

Abstract

T cell exhaustion in the tumor microenvironment

Immune checkpoint markers and CRC relevance

PD-1-based therapy limits and combination strategies

Emerging signaling pathways and challenges

Zamani etal. Cell Communication and Signaling (2026) 24:81 [https://doi.org/10.1186/s12964-025-02638-6](https://doi.org/10.1186/s12964-025-02638-6) Cell Communication and Signaling REVIEW Open Access Targeting T cell exhaustion in colorectal cancer: emerging roles of LAG-3, TIM- 3, and TIGIT signaling in overcoming immunotherapy resistance Pardis Zamani1†, Erfan Barootchi 1†, Ayda Firouzabadi2†, Maryam Sadat Tonekaboni3†, Kiarash Saleki3,4,5,6,7, Niloufar Yazdanpanah3,7 and Nima Rezaei3,7,8,9* Abstract Exhaustion ofT cells, characterized by their compromised function and cytokine production, was first discovered in chronic infections and later redefined in the context of immunosuppressed tumor microenvironment (TME) . Exhaustion markers include the immune checkpoints PD-1, TIM-3, LAG-3, and TIGIT. Colorectal cancer (CRC), which ranks among the highest in global prevalence, has been associated with exhaustion ofT cells. While many trials have focused on anti-PD1 therapeutics in clinical trials, results indicate suboptimal efficacy. A robust approach involved dual blockade of other immune checkpoints together with PD-1 . Interestingly, novel exhaustion markers could be used as prognostic markers for the development and progression of CRC. The present work discusses the basics ofT cell exhaustion markers and their signaling in CRC. Also, novel combination therapy approaches and challenges in the field are discussed. Keywords Colorectal cancer, T cell exhaustion, Immune checkpoint, Immunotherapy | †Pardis Zamani and Erfan Barootchi are co-first authorship and contributed equally to the present work. | | --- | | †Ayda Firouzabadi and Maryam Sadat Tonekaboni are co-second authorship and contributed equally to the present work. | *Correspondence: Nima Rezaei [rezaei_nima@tums.ac.ir](rezaei_nima@tums.ac.ir); [rezaei_nima@yahoo.com](rezaei_nima@yahoo.com) 1School of Medicine, Tehran University of Medical Sciences, Tehran, Iran 2Afzalipour Faculty of Medicine, Student Research Committee, Kerman University of Medical Sciences, Kerman, Iran 3Network of Immunity in Infection, Malignancy and Autoimmunity (NIIMA), Universal Scientific Education and Research Network (USERN), Tehran, Iran 4Student Research Committee, Babol University of Medical Sciences, Babol, Iran 5USERN Office, Babol University of Medical Sciences, Babol, Iran 6School of Medicine, Tehran University of Medical Sciences, Tehran, Iran 7Research Center for Immunodeficiencies, Children’s Medical Center, Tehran University of Medical Sciences, Tehran, Iran 8Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran 9Tehran University of Medical Sciences, Children’s Medical Center Hospital, Dr. Qarib St, Keshavarz Blvd, Tehran 14194, Iran © The Author(s) 2026. Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit [http://creati](http://creati)[vecommons.org/licenses/by-nc-nd/4.0/](vecommons.org/licenses/by-nc-nd/4.0/.)[.](vecommons.org/licenses/by-nc-nd/4.0/.) Zamani et al. Cell Communication and Signaling

FAQs

What defines T cell exhaustion in the context of colorectal cancer?

T cell exhaustion is characterized by compromised T cell function and reduced cytokine production, influenced by the immunosuppressive tumor microenvironment in colorectal cancer.

Which immune checkpoint markers are discussed as exhaustion markers?

The review highlights PD-1, TIM-3, LAG-3, and TIGIT as key exhaustion-associated immune checkpoint markers.

Why might anti-PD-1 therapies show suboptimal efficacy in colorectal cancer?

The document states that results from many anti-PD-1 focused trials indicate suboptimal efficacy, motivating alternative combination approaches with additional checkpoints.

Sep 22, 2026

Upload by Patrick