CD47-mediated tumor microenvironment remodeling: a central mechanism in immune evasion

Abstract

Immune evasion is a crucial strategy for tumor growth and survival, with the tumor microenvironment facilitating tumor immune evasion and cancer progression. CD47, a transmembrane protein highly expressed in various cancer cell types, interacts with its ligands SIRPα and TSP-1 to induce immune tolerance, enabling tumor cells to evade immune surveillance and phagocytosis by immune cells. Understanding the pathways driving CD47 signaling and related activation factors is essential. In this review, we discuss the interactions between CD47 and its ligands SIRPα and TSP-1; their roles in inhibiting the functions of immune cells (macrophages, dendritic cells (DCs), glial cells, T cells, NK cells, etc.); and the mechanisms involved. Furthermore, we also explore the influence of factors within the tumor microenvironment, including TNF-α, IFN-γ, ILs, HIF-1, oncogenes, isocitrate dehydrogenase 1, metabolic enzymes, and exosomes, on CD47-mediated immune evasion. Recent monoclonal antibody drugs targeting CD47 for cancer treatment have shown side effects and cause economic losses. Researchers can explore alternative approaches, such as designing targeted drugs with minimal side effects or investigating other related molecules or pathways. Combination therapy and further research into the molecular mechanisms of CD47 could offer new directions for antitumor drug development.

1. Introduction

Cancer not only comprises malignant cells but also includes many other cells that may be transformed. The interactions between malignant cells and nontransformed cells create the tumor microenvironment (TME), which influences cancer development [1]. In addition to malignant cells, the TME also contains immune cells, tumor vascular cells, lymphatic cells, fibroblasts, and pericytes [1]. In addition to these cells, the TME includes the extracellular matrix, such as collagen, various cytokines, growth factors, and the matrix remodeling enzyme system [2], all of which can support the process of malignant transformation. The composition and structure of the TME vary depending on the type of cancer and the patient. The TME consists of a large population of cancer cells and nearby endogenous stromal cells that are recruited to promote tumorigenesis and progression [3]. The tumor-associated stroma provides nutrients, oxygen, and enzymes to the tumor [4]. When CD47 is expressed on fibroblasts, it can activate regulatory T cells (Tregs) and promote their immunosuppressive function, leading to a decrease in the antitumor immune response [5]. CD47 is closely correlated with the ovarian cancer immune microenvironment and might induce ovarian cancer heterogeneity [6].

Tumor cells alter the TME by reprogramming immune cells, secreting immunosuppressive factors, activating immune checkpoints (such as PD-L1, CTLA-4, and CD47), and utilizing exosomes, thereby inhibiting immune responses and promoting immune evasion. The TME can drive tumor immune evasion and cancer progression [7]. The TME influences and controls tumor growth through paracrine and juxtacrine interactions [3], impacting cancer cell invasion, tumor growth, and metastasis in this process [8].