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

## TL;DR

This review explains how cancer cells use metabolic changes to hijack the process of clearing dead cells, promoting tumor growth and immune evasion, and suggests targeting this process for better cancer treatments.

## Contribution

The paper introduces the efferocytic–metabolic axis as a novel therapeutic target in cancer immunotherapy.

## Key findings

- Tumor cells release metabolites that reshape macrophages into a pro-tumor phenotype.
- Abnormal glycosylation and lipid oxidation help tumor cells evade clearance by altering recognition signals.
- Post-engulfment metabolic shifts in macrophages sustain immunosuppression and tumor progression.

## Abstract

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.

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.

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’.

Metabolic reprogramming allows tumour cells to hijack efferocytosis for immune evasion.Metabolite release recruits and reshapes macrophages into a pro‐tumourigenic phenotype.Abnormal glycosylation and lipid oxidation modulate ‘eat‐me/don't‐eat‐me’ signals to escape clearance.Post‐efferocytic metabolic shifts sustain M2‐like polarisation, making the efferocytic–metabolic axis a vital therapeutic target.

Metabolic reprogramming allows tumour cells to hijack efferocytosis for immune evasion.

Metabolite release recruits and reshapes macrophages into a pro‐tumourigenic phenotype.

Abnormal glycosylation and lipid oxidation modulate ‘eat‐me/don't‐eat‐me’ signals to escape clearance.

Post‐efferocytic metabolic shifts sustain M2‐like polarisation, making the efferocytic–metabolic axis a vital therapeutic target.

This review systematically deconstructs the pathological efferocytic—metabolic axis in tumours, framing it as a three‐stage, self‐reinforcing cycle: from metabolite‐driven macrophage recruitment, through hijacked surface recognition, to post‐phagocytic metabolic reprogramming that locks in immunosuppression. We integrate definitive genetic evidence, delineate stage‐specific therapeutic strategies and propose that targeting this integrated metabolic network is key to reversing immune tolerance and restoring anti‐tumour immunity.