Targeting the Immunosuppressive Microenvironment in Colorectal Cancer: Pharmacological and Nanomedicine Strategies

The immunosuppressive stroma in colorectal cancer (CRC) plays a central role in therapeutic resistance. Modulating key targets within this stromal compartment has been proposed as a promising strategy for restoring antitumor immunity and overcoming resistance mechanisms. Several immunomodulatory agents, including next-generation immunotherapies, small-molecule inhibitors targeting specific receptors or signaling pathways, and natural compounds, have shown potential for remodeling the tumor immune microenvironment (TIME). In addition, nanoparticle-based delivery systems may further enhance the therapeutic efficacy of these agents. Evidence from both preclinical and clinical studies suggests that targeting stromal and immunosuppressive cells can effectively remodel the antitumor immune response in CRC. Furthermore, specific inhibitors, natural products, and their nanoformulations may enhance antitumor immunity by suppressing the recruitment and activity of immunosuppressive stromal and immune cells. This review summarizes the current knowledge of emerging pharmacological agents, including immunomodulators, therapeutic drugs, and their nanoformulations, for restoring antitumor immunity in CRC. It first discusses the fundamental immunosuppressive interactions within the TME and subsequently examines how these agents enhance immune responses by reprogramming stromal and immune cells, as well as their secreted mediators within the TIME.

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