This review explores the role of extracellular matrix (ECM) stiffness in cancer progression and the effectiveness of immunotherapy. It discusses key factors regulating ECM remodeling, including the activation of cancer-associated fibroblasts (CAFs) and the accumulation and crosslinking of ECM proteins. The review highlights how ECM stiffness influences the behavior of both tumor and immune cells, and how it affects the response to various immunotherapy strategies such as immune checkpoint blockade, adoptive cell therapy, oncolytic virus therapy, and therapeutic cancer vaccines. It also addresses the challenges in translating research findings into clinical practice, emphasizing the need for more precise biomaterials that accurately mimic the ECM and the development of novel therapeutic strategies. The insights provided aim to guide future research, with the potential to enhance the effectiveness of cancer immunotherapy modalities. The review also discusses the effects of ECM stiffness on tumor cells, immune cells, tumor-associated macrophages, and tumor endothelial cells, highlighting the critical role of biomechanical forces in regulating immune cell function. It explores strategies to target ECM stiffness to improve the efficacy of immunotherapy, including the use of ECM-degrading agents and combination therapies with immunotherapies. The review concludes with the potential of targeting ECM stiffness to overcome immune resistance and enhance the effectiveness of cancer immunotherapy.This review explores the role of extracellular matrix (ECM) stiffness in cancer progression and the effectiveness of immunotherapy. It discusses key factors regulating ECM remodeling, including the activation of cancer-associated fibroblasts (CAFs) and the accumulation and crosslinking of ECM proteins. The review highlights how ECM stiffness influences the behavior of both tumor and immune cells, and how it affects the response to various immunotherapy strategies such as immune checkpoint blockade, adoptive cell therapy, oncolytic virus therapy, and therapeutic cancer vaccines. It also addresses the challenges in translating research findings into clinical practice, emphasizing the need for more precise biomaterials that accurately mimic the ECM and the development of novel therapeutic strategies. The insights provided aim to guide future research, with the potential to enhance the effectiveness of cancer immunotherapy modalities. The review also discusses the effects of ECM stiffness on tumor cells, immune cells, tumor-associated macrophages, and tumor endothelial cells, highlighting the critical role of biomechanical forces in regulating immune cell function. It explores strategies to target ECM stiffness to improve the efficacy of immunotherapy, including the use of ECM-degrading agents and combination therapies with immunotherapies. The review concludes with the potential of targeting ECM stiffness to overcome immune resistance and enhance the effectiveness of cancer immunotherapy.