CTGF Remodels Tumor Immune Microenvironment, Impairing Antitumor Immunity and Immunotherapy Efficacy

The tumor immune microenvironment (TIME) is a critical determinant of limited efficacy and acquired resistance to current cancer immunotherapy strategies, such as immune checkpoint inhibitors (ICIs). Many malignancies exhibit a non-inflamed TIME, hindering immune cell infiltration and function. Connective tissue growth factor (CTGF), a matricellular protein, has emerged as a significant player implicated in multiple TIME-related processes, including tumor-cell phenotypic regulation, extracellular matrix (ECM) remodeling, immune-cell modulation, and cytokine-network alterations. Understanding CTGF's role is crucial for overcoming immunotherapy resistance.

This comprehensive review synthesizes existing literature to delineate the core mechanisms by which CTGF mediates TIME remodeling. The authors systematically summarized empirical evidence supporting CTGF's roles in selected tumor and stromal settings, analyzing its participation in coordinated crosstalk among structural, signaling, and immune components of the TIME. The review also outlines the translational potential of CTGF-targeted combination immunotherapies and identifies key research priorities necessary to advance its clinical translation.

The review highlights CTGF's multifaceted involvement in shaping an immunosuppressive TIME. It demonstrates how CTGF contributes to tumor-cell phenotypic regulation, promoting survival and immune evasion. Crucially, CTGF drives extensive ECM remodeling, creating physical barriers and biochemical cues that impede immune cell infiltration and function. Furthermore, CTGF directly modulates immune-cell behavior, fostering an environment conducive to tumor growth, and orchestrates cytokine-network alterations that suppress antitumor responses.

CTGF participates in coordinated crosstalk among structural, signaling, and immune components of the TIME, collectively impairing antitumor immune recognition and promoting tumor-cell survival. These coordinated effects suggest that CTGF acts as a central hub, integrating various pro-tumorigenic signals within the microenvironment. The review consolidates evidence indicating that CTGF can promote a non-inflamed or "cold" tumor phenotype, which is typically unresponsive to current immune checkpoint blockade strategies. Its influence extends to promoting angiogenesis and fibrosis, further entrenching the tumor's ability to evade immune surveillance.