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Journal of Translational Medicine (2024) 22:382  \n[https://doi.org/10.1186/s12967-024-05199-3](https://doi.org/10.1186/s12967-024-05199-3)  \nJournal of Translational Medicine  \n REVIEW Open Access  \nUnderstanding the matrix: collagen  \nmodifications in tumors and their implications for immunotherapy  \nRowie Borst 1,2, Linde Meyaard1,2 and M. Ines Pascoal Ramos 1,2,3*  \nAbstract  \nTumors 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  \non 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.  \nIntroduction  \nThe 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  \n*Correspondence:  \nM. Ines Pascoal Ramos [ines.ramos@research.fchampalimaud.org](ines.ramos@research.fchampalimaud.org)  \n1 Center for Translational Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands  \n2 Oncode Institute, Utrecht, The Netherlands  \n3 Champalimaud Research, Champalimaud Centre for the Unknown, Lisbon, Portugal  \nof 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.  \nCancer 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  \n© 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","cbCairiHeH0G2fQn","https://ap.wps.com/l/cbCairiHeH0G2fQn","pdf",1272541,15,"English","# Abstract\n# Introduction\n## ECM dynamics and collagen composition\n## Collagen stiffness and crosslinking\n## Desmoplasia and cancer-associated fibroblasts\n## EMT, immune interactions, and mechanical cues","[{\"question\":\"Why is the extracellular matrix (ECM) important in cancer and immunotherapy?\",\"answer\":\"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.\"},{\"question\":\"How do collagen post-translational modifications (PTMs) affect tumor behavior?\",\"answer\":\"Collagen PTMs alter collagen structure and functionality, impacting receptor binding, cell migration, and tumor stiffness, which collectively influence tumor progression and immune responses.\"},{\"question\":\"What therapeutic opportunities are discussed regarding collagen in tumors?\",\"answer\":\"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.\"}]","Understanding the matrix: collagen modifications in tumors and their implications for immunotherapy - review - implications and therapeutic targeting | PDF",1789989071,38]