Metabolic reprogramming of efferocytosis in the tumour microenvironment: From apoptotic-cell clearance to therapeutic targeting

Abstract

Background: Efferocytosis is a critical physiological process in which phagocytes clear apoptotic cells to maintain tissue homeostasis. However, within the tumour microenvironment (TME), this process is systematically hijacked by tumour cells, transforming it into a key pathological mechanism that drives immunosuppression, tumour progression and therapeutic resistance.

Key findings: This review systematically elucidates the central role of metabolic reprogramming in this functional reversal, emphasising that efferocytosis is essentially an immunometabolic intersection process precisely regulated by metabolism. By releasing various metabolites such as ATP, lactate, adenosine and sphingosine-1-phosphate (S1P), apoptotic tumour cells not only recruit tumour-associated macrophages (TAMs) but also metabolically pre-program their functions, inducing polarisation towards a pro-tumourigenic M2-like phenotype. During the recognition stage, tumour cells exploit metabolic abnormalities, such as glycosylation and lipid oxidation, to modify surface ‘eat-me/don't-eat-me’ signals, thereby hijacking macrophage recognition and engulfment programs. Upon completion of engulfment, systemic reprogramming of amino acid, lipid and glucose metabolism occurs within macrophages. These metabolic alterations synergistically lock their immunosuppressive phenotype and establish a metabolic symbiosis between the tumour and stromal cells.

Conclusions: Based on these mechanisms, this review further explores translational strategies targeting the efferocytic–metabolic axis, aiming to reprogram the immunosuppressive efferocytosis into immune-activating events to overcome TME-mediated immunosuppression and enhance current therapeutic efficacy. By deeply dissecting the metabolic regulatory networks of efferocytosis, we aim to pave new directions for cancer immunotherapy, achieving a paradigm shift from ‘metabolic hijacking’ to ‘metabolic interventional therapy’.

Keywords

Cancer immunotherapy / Efferocytosis / Immunometabolism / Metabolic reprogramming / Tumour microenvironment (TME)

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