结直肠癌（CRC）肿瘤微环境（TME）内基质硬度的增加已成为免疫治疗结果的关键决定因素。这篇综述讨论了异常细胞外基质 (ECM) 沉积和交联在增加基质刚度方面的作用，这种现象不仅支撑肿瘤结构，而且还有助于致瘤性和免疫逃避。在此，我们批判性地评估了基质硬度对结直肠癌免疫治疗前景的影响，重点关注其通过调节免疫细胞浸润、激活和功能表现来阻碍治疗效果的能力。该综述探讨了基质刚度促进肿瘤进化的分子动力学，强调了整合素信号传导、癌症相关成纤维细胞 (CAF) 和上皮间质转化 (EMT) 过程的不可或缺的作用。我们突出了硬化 ECM 对免疫效应细胞（主要是 T 细胞和巨噬细胞）的矛盾影响，这些细胞对于免疫监视和免疫治疗策略的执行是必不可少的，但受到纤维化基质的明显抑制。此外，我们还研究了基质硬度如何调节免疫检查点分子表达，从而加剧 TME 内的免疫抑制环境并削弱免疫治疗效力。针对基质刚度的紧急治疗方案，包括基质调节剂、机械转导信号通路抑制剂以及模仿 ECM 的先进生物材料，提供了增强免疫治疗反应性的新模式。通过改善ECM的生物力学属性，可以改善肿瘤基质构成的机械屏障，促进免疫细胞的强大渗透和活性，从而增强肿瘤对免疫治疗的敏感性。正在进行的临床试验正在评估这些创新疗法，特别是与免疫疗法相结合，目的是改善患有明显基质僵硬的 CRC 患者的临床结果。版权所有 © 2024 Elsevier B.V. 保留所有权利。

Increased matrix stiffness within the colorectal cancer (CRC) tumor microenvironment (TME) has emerged as a pivotal determinant of immunotherapy outcomes. This review discusses the role of aberrant extracellular matrix (ECM) deposition and cross-linking in augmenting matrix stiffness, a phenomenon that not only scaffolds the tumor architecture but also contributes to tumorigenicity and immunologic evasion. Herein, we critically appraise the influence of matrix stiffness on the immunotherapeutic landscape of CRC, focusing on its capacity to impede therapeutic efficacy by modulating immune cell infiltration, activation, and functional performance. The review explores the molecular dynamics whereby matrix stiffness prompts tumor evolution, highlighting the integral role of integrin signaling, cancer-associated fibroblasts (CAFs), and the process of epithelial-mesenchymal transition (EMT). We bring to the fore the paradoxical impact of an indurated ECM on immune effector cells, chiefly T cells and macrophages, which are indispensable for immune surveillance and the execution of immunotherapeutic strategies, yet are markedly restrained by a fibrotic matrix. Furthermore, we examine how matrix stiffness modulates immune checkpoint molecule expression, thereby exacerbating the immunosuppressive milieu within the TME and attenuating immunotherapeutic potency. Emergent therapeutic regimens targeting matrix stiffness-including matrix modulators, inhibitors of mechanotransduction signaling pathways, and advanced biomaterials that mimic the ECM-proffer novel modalities to potentiate immunotherapy responsiveness. By refining the ECM's biomechanical attributes, the mechanical barriers posed by the tumor stroma can be improved, facilitating robust immune cell penetration and activity, and thereby bolstering the tumor's susceptibility to immunotherapy. Ongoing clinical trials are evaluating these innovative treatments, particularly in combination with immunotherapies, with the aim of enhancing clinical outcomes for CRC patients afflicted by pronounced matrix stiffness.Copyright © 2024 Elsevier B.V. All rights reserved.