Frontier knowledge and future directions of programmed cell death in clear cell renal cell carcinoma

Abstract

Clear cell renal cell carcinoma (ccRCC) is one of the most common renal malignancies of the urinary system. Patient outcomes are relatively poor due to the lack of early diagnostic markers and resistance to existing treatment options. Programmed cell death, also known as apoptosis, is a highly regulated and orchestrated form of cell death that occurs ubiquitously throughout various physiological processes. It plays a crucial role in maintaining homeostasis and the balance of cellular activities. The combination of immune checkpoint inhibitors plus targeted therapies is the first-line therapy to advanced RCC. Immune checkpoint inhibitors(ICIs) targeted CTLA-4 and PD-1 have been demonstrated to prompt tumor cell death by immunogenic cell death. Literatures on the rationale of VEGFR inhibitors and mTOR inhibitors to suppress RCC also implicate autophagic, apoptosis and ferroptosis. Accordingly, investigations of cell death modes have important implications for the improvement of existing treatment modalities and the proposal of new therapies for RCC. At present, the novel modes of cell death in renal cancer include ferroptosis, immunogenic cell death, apoptosis, pyroptosis, necroptosis, parthanatos, netotic cell death, cuproptosis, lysosomal-dependent cell death, autophagy-dependent cell death and mpt-driven necrosis, all of which belong to programmed cell death. In this review, we briefly describe the classification of cell death, and discuss the interactions and development between ccRCC and these novel forms of cell death, with a focus on ferroptosis, immunogenic cell death, and apoptosis, in an effort to present the theoretical underpinnings and research possibilities for the diagnosis and targeted treatment of ccRCC.

Fig. 1. Metabolism and cell signaling associated with ferroptosis in ccRCC cell.

The figure illustrates the relationship between HIF, ferroptosis, and metabolic pathways in ccRCC. HIF is involved in the metabolic reprogramming of ccRCC cells under hypoxia, and one of the “side effects” is that it increases tumor cells’ vulnerability to ferroptosis through a variety of metabolism pathways. To resist ferroptosis, ccRCC cells stimulate glutathione (GSH) production by raising the expression of glutathione metabolism target genes and inhibit acyl-CoA synthetase long chain family member 4 (ACSL4) expression. Abbreviations: TfR transferrin receptor, ROS reactive oxygen species, TCA mitochondrial TCA cycle, Gln glutamine, Glu glutamate, α-KG α-ketoglutarate, Gly glycine, PUFA polyunsaturated fatty acids, GSSG oxidized glutathione, GPX4 glutathioneperoxidase-4, GLUT1 Glucose transporter 1, LPCAT3 lysophosphatidylcholine acyltransferase 3, POR cytochrome P450 oxidoreductase, LOX lipoxygenase, GGT γ -glutamyl transferase, GCL glutamate cysteine ligase, GSS GSH synthetase.

Fig. 2. Heating up “cold” tumors.

ccRCC cells that suffer immunogenic cell death (ICD) or other forms of cell death in response to drugs or other stresses can release tumor-associated antigens, cytokines, and damage-associated molecular patterns (DAMPs) that promote recruitment, phagocytic activity and maturation of innate immune cells. Among these cells, antigen-presenting cells (APCs) migrate to lymph nodes to prime adaptive immunity, therefore suppressing ccRCC tumor development and lowering the risk of metastasis. Abbreviations: LPS Lipopolysaccharide, CRT calreticulin, HMGB1 high-mobility group protein box 1, HSP heat shock protein, DC dendritic cell, NK natural killer cell, IFN interferon, ICI immune checkpoint inhibitor.

Fig. 3. Some mechanisms of cell death in ccRCC cell.

Abbreviations: ER endoplasmic reticulum, PARP 1 Poly (ADP-Ribose) polymerase 1, ADCD Autophagy-dependent cell death, LDCD Lysosomal-dependent cell death, LPS lipopolysaccharide, MLKL mixed-lineage kinase domain-like protein, LMP lysosomal membrane permeabilization, MPT mitochondrial permeability transition, GPX 4 Glutathionperoxidase-4, DAMPs (damage-associated molecular patterns), PARP1 (Poly (ADP-Ribose) polymerase 1), RIPK3 (receptor-interacting serine/threonine protein kinase 3), RIPK1 (receptor-interacting serine/threonine protein kinase 1), LP (lipoylated proteins).