Collagen in the tumor microenvironment plays diverse biological roles, from serving as the structural framework of tumors to influencing immune responses, angiogenesis, and tumor progression. Consequently, developing strategies to optimize the suppression of collagen's promotive effects on tumor growth while maintaining its inhibitory functions on tumor initiation has become a key focus of cancer research and therapy. A significant challenge remains in identifying a biomarker with both high sensitivity and specificity for cancer diagnosis. This review, therefore, highlights the substantial value and clinical relevance of collagen as a biomarker throughout cancer onset and progression. It explores the fundamental link between collagen and immunotherapeutic outcomes, further illustrating how targeting collagen-along with its interactions with tumors and immune cells-can offer more reliable predictive markers for personalized immunotherapy. This approach ultimately enables the development of more tailored and standardized treatment regimens for patients with cancer.