The role of cisplatin in modulating the tumor immune microenvironment and its combination therapy strategies: a new approach to enhance anti-tumor efficacy

Abstract

Cisplatin is a platinum-based drug that is frequently used to treat multiple tumors. The anti-tumor effect of cisplatin is closely related to the tumor immune microenvironment (TIME), which includes several immune cell types, such as the tumor-associated macrophages (TAMs), cytotoxic T-lymphocytes (CTLs), dendritic cells (DCs), myeloid-derived suppressor cells (MDSCs), regulatory T cells (Tregs), and natural killer (NK) cells. The interaction between these immune cells can promote tumor survival and chemoresistance, and decrease the efficacy of cisplatin monotherapy. Therefore, various combination treatment strategies have been devised to enhance patient responsiveness to cisplatin therapy. Cisplatin can augment anti-tumor immune responses in combination with immune checkpoint blockers (such as PD-1/PD-L1 or CTLA4 inhibitors), lipid metabolism disruptors (like FASN inhibitors and SCD inhibitors) and nanoparticles (NPs), resulting in better outcomes. Exploring the interaction between cisplatin and the TIME will help identify potential therapeutic targets for improving the treatment outcomes in cancer patients.

Keywords: Cisplatin; combination therapy; immune therapy; lipid metabolism disruptors; tumor immune microenvironment.

Figure 1.

Mechanism of action for cisplatin. (1) Cisplatin enters tumor cells via CTR1 or passive diffusion. Cisplatin enters the nucleus and cross-links with DNA molecules, leading to apoptosis. (2) Cisplatin leads to mitophagy through the production of ROS, which leads to apoptosis. (3) Cisplatin activates the Fas receptor pathway, which activates Casp8 downstream, thereby stimulating Casp3 and promoting apoptosis. CTR1: copper transporter 1, ROS: reactive oxygen species, Casp3: caspase 3, Casp8: caspase 8, FasL: Fas ligand, FADD: Fas-associated death domain. Created with BioRender.com.

Figure 2.

Effect of cisplatin on the TIME. (1) Cisplatin promotes M1 polarization of TAMs by increasing the secretion of IFN-γ and TNF-α. (2) Cisplatin treatment of tumor cells produces type I IFN, which upregulates costimulatory molecules on APCs and promotes the activation of CTLs.(3) cisplatin potentially induces the differentiation of MDSCs into DCs by increasing the expression of DC markers such as CD40, CD80, and CD86.(4) cisplatin promotes exosome secretion by CAFs, which inhibits ferroptosis in tumor cells by reducing the accumulation of ROS, thereby increasing resistance to cisplatin. IFN-γ: interferon-γ, TNF-α: tumor necrosis factor-α, TAM: tumor-associated macrophage, APC: antigen-presenting cell, CTL: cytotoxic T-lymphocyte, MDSC: myeloid-derived suppressor cell, DC: dendritic cell, CAF: cancer-associated fibroblasts, ROS: reactive oxygen species. Created with BioRender.com.

Figure 3.

Effect of cisplatin and immune checkpoint inhibitors on immune checkpoints. T cells recognize the MHC-I molecules through their surface TCR, leading to T cell activation. However, PD-1 and CTLA-4 on T cells bind to PD-L1 and CD80 on tumor cells to inhibit T cell activation. In addition, cisplatin resistance can lead to upregulation of PD-1 to inhibit T cell activation and thus promote tumor cell proliferation. PD-1/PD-L1 and CTLA-4 inhibitors inhibit the binding of PD-1 to PD-L1 and CTLA-4 to CD80, thereby promoting T cell activation and tumor cell death. MHC-I: major histocompatibility complex class I, TCR: T cell receptors, PD-1: programmed death receptor 1, PD-L1: programed death ligand 1, CTLA-4: cytotoxic T lymphocyte-associated protein 4, CD80: cluster of differentiation 80. Created with BioRender.com.

Figure 4.

Cisplatin, FASN inhibitors, and SCD inhibitors work together to regulate fatty acid biosynthesis pathways. Glucose is phosphorylated to Glucose-6-phosphate by hexokinase when ingested by tumor cells and enters the glycolytic pathway. The pyruvate produced enters the mitochondria and enters the TCA cycle, and the resulting succinic acid activates HIF-1α. FASN enhances transcription of SLC7A11 by binding to HIF-1α. FASN inhibitors block this process, inhibiting the transcription of SLC7A11. In addition, acetyl-CoA produced by pyruvate is converted to malonyl-CoA. Using NADPH as a reducing cofactor, FASN catalyzes the synthesis of palmitic acid by acetyl-CoA and malonyl-CoA, which then synthesize FAs to participate in a variety of biological processes. Cisplatin and FASN inhibitors reduce FASN expression, reduce FAs synthesis and increase apoptosis of tumor cells. Cisplatin and SCD inhibitors also reduce FAs synthesis and increase apoptosis in tumor cells. TCA: tricarboxylic acid, FASN: Fatty acid synthase, FASNi: Fatty acid synthase inhibitors, SCD: Stearoyl-CoA desaturase, SCDi: Stearoyl-CoA desaturase inhibitors, HIF-1α: Hypoxia-inducible factor-1α, SLC7A11: Solute carrier family 7 member 11, NADPH: Nicotinamide adenine dinucleotide phosphate, FAs: fatty acids. Created with BioRender.com.