Understanding the matrix: collagen modifications in tumors and their implications for immunotherapy - review - implications and therapeutic targeting

Sep 21, 2026

Tumors are complex, heterogeneous ecosystems in which malignant cells interact with healthy cells and the surrounding extracellular matrix (ECM). Solid tumors contain extensive ECM deposits that can reach about 60% of tumor mass, supporting cancer survival, growth, and immune-therapy responses. Collagen is the most abundant ECM protein family, with 28 subtypes capable of post-translational modifications (PTMs). These PTMs change collagen structure and function, influencing receptor binding, cell migration, tumor stiffness, and ultimately tumor immune responses. Targeting collagen and cell-ECM interactions offers therapeutic potential.

LanguageEnglish

CategoryResearch & Report

FormatPDF

Pages15

Reading Time38 min

AccessFree to download

Abstract

Introduction

ECM dynamics and collagen composition

Collagen stiffness and crosslinking

Desmoplasia and cancer-associated fibroblasts

EMT, immune interactions, and mechanical cues

Borst et al. Journal of Translational Medicine (2024) 22:382 [https://doi.org/10.1186/s12967-024-05199-3](https://doi.org/10.1186/s12967-024-05199-3) Journal of Translational Medicine REVIEW Open Access Understanding the matrix: collagen modifications in tumors and their implications for immunotherapy Rowie Borst 1,2, Linde Meyaard1,2 and M. Ines Pascoal Ramos 1,2,3* Abstract Tumors are highly complex and heterogenous ecosystems where malignant cells interact with healthy cells and the surrounding extracellular matrix (ECM) . Solid tumors contain large ECM deposits that can constitute up to 60% of the tumor mass. This supports the survival and growth of cancerous cells and plays a critical role in the response to immune therapy. There is untapped potential in targeting the ECM and cell-ECM interactions to improve existing immune therapy and explore novel therapeutic strategies. The most abundant proteins in the ECM are the collagen family. There are 28 different collagen subtypes that can undergo several post-translational modifications (PTMs), which alter both their structure and functionality. Here, we review current knowledge on tumor collagen composition and the consequences of collagen PTMs affecting receptor binding, cell migration and tumor stiffness. Furthermore, we discuss how these alterations impact tumor immune responses and how collagen could be targeted to treat cancer. Introduction The extracellular matrix (ECM) is a constantly evolving structure that is produced, modified, remodeled and maintained by the cells residing within it. The ECM is dynamic and responds to changes in the local and systemic environment, making it a central player in tissue physiology and pathology such as cancer [1]. Tissues have unique ECM compositions tailored to their specific mechanical and structural demands which can be further modified in pathological conditions. The main component of the ECM are collagens consisting of 28 different types [2]. During homeostasis, the biophysical properties *Correspondence: M. Ines Pascoal Ramos [ines.ramos@research.fchampalimaud.org](ines.ramos@research.fchampalimaud.org) 1 Center for Translational Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands 2 Oncode Institute, Utrecht, The Netherlands 3 Champalimaud Research, Champalimaud Centre for the Unknown, Lisbon, Portugal of collagen are critical for maintaining tissue integrity. Collagen stiffness is influenced by the size of its fibers; short fibers offer a greater range of orientation possibilities, enhancing tissue permeability, while long fibers align closely, resulting in cells organizing in the same orientation within the tissue [3]. This close alignment facilitates the formation of collagen crosslinks contributing to increased ECM stiffness [4]. In the context of tissue repair, additional collagen crosslinks serve as a protective mechanism to aid wound closure. Cancer is viewed as a form of excessive wound-healing as similar pathways are activated in wound healing and tumorigenesis [5]. For instance, dense ECM that forms part of the scar tissue in wound healing is similar to collagen deposits known as desmoplasia in cancer, which correlate with poor prognosis [5, 6]. During tumor development, desmoplasia is induced by cancer-associated fibroblasts (CAF), macrophages and tumor cells and the produced collagen is resistant to enzymatic degradation [7–11]. CAFs are the main players in collagen remodeling in cancer. These are highly activated fibroblasts and © The Author(s) 2024. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, 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 changes were made. The images or other third party mat

FAQs

Why is the extracellular matrix (ECM) important in cancer and immunotherapy?

The ECM is dynamic and shapes tissue physiology and pathology. In cancer, abundant ECM deposits support tumor survival and growth and strongly influence how tumors respond to immune therapy.

How do collagen post-translational modifications (PTMs) affect tumor behavior?

Collagen PTMs alter collagen structure and functionality, impacting receptor binding, cell migration, and tumor stiffness, which collectively influence tumor progression and immune responses.

What therapeutic opportunities are discussed regarding collagen in tumors?

The review highlights untapped potential in targeting ECM and cell-ECM interactions. It specifically considers how collagen alterations could be used to improve existing immunotherapies and explore novel strategies.

Sep 21, 2026

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