Regulation of efferocytosis as a novel cancer therapy

Abstract

Efferocytosis is a physiologic phagocytic clearance of apoptotic cells, which modulates inflammatory responses and the immune environment and subsequently facilitates immune escape of cancer cells, thus promoting tumor development and progression. Efferocytosis is an equilibrium formed by perfect coordination among "find-me", "eat-me" and "don't-eat-me" signals. These signaling pathways not only affect the proliferation, invasion, metastasis, and angiogenesis of tumor cells but also regulate adaptive responses and drug resistance to antitumor therapies. Therefore, efferocytosis-related molecules and pathways are potential targets for antitumor therapy. Besides, supplementing conventional chemotherapy, radiotherapy and other immunotherapies with efferocytosis-targeted therapy could enhance the therapeutic efficacy, reduce off-target toxicity, and promote patient outcome. Video abstract.

Keywords: Antitumor therapy; CD47; Efferocytosis; Immunosuppression; Phosphatidylserine; Phosphatidylserine receptor; Tumor progression.

Fig. 1

Schematic representation of signaling pathways in the efferocytosis-induced immune suppression for tumor progression. The engulfment of apoptotic cells by tumor-associated macrophages triggers a series of signaling pathways, subsequently induces M2 polarization of macrophages while inhibiting M1 polarization, increases Treg cells while decreasing CD8+ T cells, and thereby resulting in the inflammation resolution and immune suppression, which may provide an environment for cancer to escape from immunological surveillance and promote tumor progression. NFκB = factor-κ-gene binding; JAK/STAT1 = Janus kinase/signal transducers and activators of transcription 1; PI3K/Akt = phosphatidylinositol 3 kinase/protein-serine-threonine kinase; PD-1/PD-L1 = programmed death-ligand 1/programmed cell death protein 1; TLR = Toll-like receptor; IL = interleukin; TGFβ = transforming growth factor-beta; PGE2 = prostaglandin E2; PAF = platelet-activating factor; TNF-α = tumor necrosis factor-alpha; Treg cells = regulatory t cell