The review discusses the critical role of extracellular matrix (ECM) stiffness in cancer progression and the efficacy of immunotherapy. Key factors regulating ECM remodeling include the activation of cancer-associated fibroblasts (CAFs) and the accumulation and crosslinking of ECM proteins. ECM stiffness significantly influences tumor and immune cell behaviors, such as morphology, proliferation, metabolic reprogramming, epithelial-mesenchymal transition (EMT), invasion, metastasis, and drug resistance. The review also explores how ECM stiffness affects the response to various immunotherapy strategies, including immune checkpoint blockade (ICB), adoptive cell therapy (ACT), oncolytic virus therapy (OVT), and therapeutic cancer vaccines (TCVs). Challenges in translating research findings into clinical practice are highlighted, emphasizing the need for more precise biomaterials and novel therapeutic strategies. The insights provided aim to guide future research and enhance the effectiveness of cancer immunotherapy modalities.The review discusses the critical role of extracellular matrix (ECM) stiffness in cancer progression and the efficacy of immunotherapy. Key factors regulating ECM remodeling include the activation of cancer-associated fibroblasts (CAFs) and the accumulation and crosslinking of ECM proteins. ECM stiffness significantly influences tumor and immune cell behaviors, such as morphology, proliferation, metabolic reprogramming, epithelial-mesenchymal transition (EMT), invasion, metastasis, and drug resistance. The review also explores how ECM stiffness affects the response to various immunotherapy strategies, including immune checkpoint blockade (ICB), adoptive cell therapy (ACT), oncolytic virus therapy (OVT), and therapeutic cancer vaccines (TCVs). Challenges in translating research findings into clinical practice are highlighted, emphasizing the need for more precise biomaterials and novel therapeutic strategies. The insights provided aim to guide future research and enhance the effectiveness of cancer immunotherapy modalities.