Non-apoptotic regulated cell death mediates reprogramming of the tumour immune microenvironment by macrophages

Abstract

Tumour immune microenvironment (TIME) plays an indispensable role in tumour progression, and tumour-associated macrophages (TAMs) are the most abundant immune cells in TIME. Non-apoptotic regulated cell death (RCD) can avoid the influence of tumour apoptosis resistance on anti-tumour immune response. Specifically, autophagy, ferroptosis, pyroptosis and necroptosis mediate the crosstalk between TAMs and tumour cells in TIME, thus reprogram TIME and affect the progress of tumour. In addition, although some achievements have been made in immune checkpoint inhibitors (ICIs), there is still defect that ICIs are only effective for some people because non-apoptotic RCD can bypass the apoptosis resistance of tumour. As a result, ICIs combined with targeting non-apoptotic RCD may be a promising solution. In this paper, the basic molecular mechanism of non-apoptotic RCD, the way in which non-apoptotic RCD mediates crosstalk between TAMs and tumour cells to reprogram TIME, and the latest research progress in targeting non-apoptotic RCD and ICIs are reviewed.

Keywords: autophagy; ferroptosis; immunotherapy; necroptosis; non‐apoptotic regulated cell death; pyroptosis; tumour immune microenvironment; tumour‐associated macrophages.

FIGURE 1

Mechanism of ferroptosis and autophagy. Above is the regulatory pathway of iron death. Intracellular iron overload leads to the accumulation of ROS, which in turn peroxides polyunsaturated fatty acids on the cell membrane and damages the cell membrane. The Xc‐system of cell membrane can transport cystine into the cell to synthesize GSH, and under the catalysis of GPX4, it can remove ROS from the cell and reduce the peroxidized polyunsaturated fatty acids. These two systems are antagonistic to each other and jointly regulate iron death. Below is the regulation pathway of autophagy. Cells sense ATP/AMP signals in the surrounding environment, activate downstream signal transduction through mTOR and AMPK related signal molecules and induce the formation of autophagy. Then autophagy combines with lysosomes to degrade the internal substances and release nutrients for cell recycling.

FIGURE 2

Mechanism of pyroptosis and necroptosis. Above is the regulation pathway of pyroptosis. The activation of inflammatory corpuscles will activate intracellular caspases. GSDMD protein is cleaved by activated caspases to form GSDMD‐NT with perforation activity, which forms tiny pores on the cell membrane, changes the osmotic pressure inside the cell and promotes the occurrence of apoptosis. At the same time, inflammatory factors activated in cells will also be released to the extracellular space through pores, triggering inflammatory reactions. Below is the regulatory pathway of necroptosis. After TNFR on the cell membrane binds to the ligand, it starts the assembly of intracellular complex and phosphorylates the downstream MLKL. Phosphorylated MLKL has perforation activity, forming pores on the cell membrane and inducing necrotic apoptosis.

FIGURE 3

Autophagy mediates macrophage reprogramming of the tumour immune microenvironment hypoxia and ROS in TME initiate macrophage autophagy, increase extracellular ATP concentration, promote NK cell and macrophage infiltration and reduce IFN‐1 secretion and T‐cell infiltration. At the same time, the phagocytosis of macrophages was reduced by CD47/SIRPα. DAMPs, CCL2 and IL‐6 can also trigger macrophage NF‐κB to mediate autophagy, chemotactic macrophage differentiation to M2 phenotype and reduce the release of inflammatory factors. Notably, autophagy‐secreted TRAPs also can chemotactic the M2 phenotype of macrophages. In addition, the enhancement of macrophage autophagy can effectively block the accumulation of DAMPs in mitochondria and avoid starting the focal death pathway to secrete pro‐inflammatory factors such as IL‐1β and IL‐18. The clearance of apoptotic cells by TIM4 will trigger autophagy mediated by LCA pathway in macrophages to promote the secretion of anti‐inflammatory factors and inhibit the secretion of pro‐inflammatory factors. To sum up, the effect of autophagy secretion of tumour cells on macrophages and autophagy of macrophages themselves will promote the polarization of macrophages into M2 phenotype and promote tumour metastasis and angiogenesis.

FIGURE 4

Ferroptosis mediates macrophage reprogramming of the tumour immune microenvironment. DAMPs released by ferroptosis of tumour cells will affect the polarization direction of macrophages in TME. In addition, the spontaneous ferroptosis of macrophages has a strong correlation with maintaining the iron balance of red blood cells, TP53 polymorphism and downregulation of NCOA4 expression. Polarized macrophages (M1 phenotype and M2 phenotype) in tumour microenvironment can play a role in direct contact with CD8+T cells. M1 phenotype can activate CTL to secrete IFN‐γ and inhibit the function of XC antioxidant system and produce a large number of peroxides to promote Fenton reaction and ROS accumulation in tumour cells, thus accelerate ferroptosis in tumour cells. M2 phenotype can directly contact T cells to inhibit the activation of CTL reduce the production of IFN‐γ and play an immunosuppressive role. Paradoxically, TGF‐β and IL‐6 secreted by M2 phenotype play an anti‐tumour role in XC antioxidant system by inhibiting the transcription of SLC7A11 and the function of GPX4, respectively.

FIGURE 5

Pyroptosis mediates macrophage reprogramming of the tumour immune microenvironment. The effector of tumour cell pyroptosis has the ability to reshape tumour immune microenvironment. ATP initiates macrophages to secrete IL‐8 to recruit neutrophils for infiltration, and IL‐1β promotes antigen presentation mediated by DC cells to prepare for T‐cell infiltration. In addition, it can also promote the functional activation of NK cells and CD4+ T cells and chemotaxis of macrophages to polarize M1 phenotype. The secretion of macrophages can crosstalk with other tumour cells in tumour microenvironment, which promotes the progress of tumour cell pyroptosis. TNF‐α can bind to the receptor on the surface of tumour cells, activate the pyroptosis of tumour cells through two different pathways and enhance the occurrence of anti‐tumour immune response. In addition, IL‐1α, IL‐1β, ATP and HMGB1 can all complete the pyroptosis of tumour cells by stimulating inflammatory body NLRP3. It is worth noting that GZMB has higher cutting efficiency than GZMA, which is helpful to inhibit tumour progression.