Therapeutic Strategies Targeting the Tumor–Stromal Microenvironment in Colorectal Cancer: A Narrative Review

Despite advances in colorectal cancer (CRC) treatment, outcomes in advanced disease remain poor. Current therapies mainly target the epithelial compartment of the tumor, yet increasing evidence highlights the tumor microenvironment (TME), particularly the tumor stroma, as a prognostic and potentially predictive factor. This narrative review summarizes current evidence on stromal features as biomarkers and therapeutic targets in CRC. These stromal markers, such as fibroblast-associated protein (FAP), are associated with adverse outcomes, underscoring their clinical relevance. However, therapies directly targeting these stromal components have largely failed to improve survival as single agents. Combination strategies, stromal modulation integrated with established treatments, appear more promising. However, to date, stromal targeting remains challenging and has not led to standard-of-care treatment options. This highlights the need for more effective agents, the rational design of combination strategies, and improved patient selection. Combining stroma modulators with standard therapy, guided by stromal biomarkers, may enhance efficacy and help overcome the TME-induced resistance.