Radiotherapy elicits immunogenic cell death and metabolic shifts in the tumor microenvironment: implications for immunotherapy

Abstract

Radiotherapy, one of the most utilized strategies to combat malignancies, has been constantly explored for its effectiveness and optimized, and it is currently operating at the molecular level. The tumor microenvironment (TME), where complicated changes take place under radiotherapy and other treatments, inevitably draws our attention to metabolic alterations, immunogenic cell death (ICD) and immunological interactions. In response to radiotherapy, tumor metabolism promotes DNA and membrane repair processes and reduces oxidative stress, thereby collectively alleviating the occurrence of cell death. Moreover, the induction of pyroptosis, necroptosis and ferroptosis under radiotherapy has the potential to increase antitumor immunity. Therefore, comprehensive knowledge about how radiotherapy triggers these modalities of ICD mechanically is necessary for developing nanomedicines with more accurate targets. In addition, information on clinical advancements as well as the management of adverse events is important for investigating radiotherapy combined with immunotherapy. This review provides an overview of up-to-date findings on metabolic changes and ICD under radiotherapy and provides insight into the status of the TME.

Keywords: immunogenic cell death; immunotherapy; metabolism; radiotherapy; tumor microenvironment.

Figure 1

Several changes in the tumor microenvironment (TME) occur during radiotherapy. The acidity of the TME is attributed mainly to glycolysis in cancer cells and is sensed by macrophages, leading to macrophage polarization. ICD in tumors caused by radiotherapy releases DAMPs, including ATP, CRT and HMGB1, which help with the initiation of adaptive immunity. Radiotherapy has different effects on various types of immune cells, such as upregulating the expression of PD-L1 in MDSCs and increasing the number of NKALs specific for NKG2D. Radiotherapy also affects the pattern and efficiency of blood vessel development in a dose-dependent manner. ICD, immunogenic cell death; DAMPs, damage-associated molecular patterns; ATP, adenosine triphosphate; CRT, calreticulin; HMGB1, high-mobility group box-1 protein; DCs, dendritic cells; PD-L1, programmed death ligand 1; MDSCs, myeloid-derived suppressor cells; NKALs, NK cell-activating ligands; NKG2D, natural killer group 2 member D.

Figure 2

Radiotherapy-mediated metabolic shifts within the TME. Radiotherapy triggers tumor metabolic rewiring to enhance survival. Glycolysis fuels ATP, while PKM2 inactivation diverts intermediates to the PPP and SSP. Glutamine metabolism supports nucleotide and glutathione synthesis via GLS. Enhanced lipogenesis and lipid scavenging from stromal cells (e.g., CAFs and adipocytes) aid membrane repair. Tumor-secreted ROS and lactate suppresses immune activity, while stromal cells supply nutrients, fostering therapy resistance. Abbreviations: PKM2, pyruvate kinase M2; PPP, pentose phosphate pathway; SSP, serine synthesis pathway; GLS, glutaminolysis; CAF, cancer-associated fibroblast; ROS, reactive oxygen species.

Figure 3

Mechanisms of immunogenic cell death modalities under radiotherapy. The types of pyroptosis induced by radiotherapy include the inflammasome-caspase 1-GSDMD pathway and the caspase 3-GSDME pathway. Necroptosis elicited by radiotherapy mainly relies on a ZBP1-mediated pathway. Ferroptosis, which involves the executive and suppressive systems, is driven by lipid peroxidation, which can be facilitated by radiotherapy and the consequential increase in ROS. ACSL4 and GPX4 are known targets of radiotherapy. DAMPs, damage-associated molecular patterns; ROS, reactive oxygen species; AIM2, absent in melanoma 2; NLRP3, NOD-, LRR- and pyrin domain-containing protein 3; ZBP1, Z-DNA-binding protein 1; RIPK1, receptor-interacting protein kinase 1; RIPK3, receptor-interacting protein kinase 3; MLKL, mixed lineage kinase domain-like protein; TfR1, transferrin receptor 1; STEAP, six-transmembrane epithelial antigen of prostate; PUFA-PL, polyunsaturated fatty acid-containing phospholipid; ACSL4, acyl-CoA synthetase long chain family member 4; LPCAT3, lysophosphatidylcholine acyltransferase 3; GPX4, glutathione peroxidase 4; GSH, glutathione; GSSG, oxidized glutathione.