Table 2.

Applications of programmed cell death pathways in immunotherapy for TNBC

Cell death pathway involved	Drugs or molecules	Mechanism	References
Apoptosis	PD-1/PD-L1 inhibitors	Inhibiting the interaction between PD-1 and PD-L1 boosts T cell activity, enabling immune cells to more effectively identify and destroy tumor cells, thereby encouraging tumor cell apoptosis	[376]
	anti-CTLA-4 antibody	Inhibiting the CTLA-4 immune checkpoint pathway decreases Treg cell numbers, boosts T cell activation and proliferation, and encourages tumor cell apoptosis	[377]
	IFN-γ	IFN-γ induces endoplasmic reticulum stress thereby hindering the formation of autophagosomes, resulting in the misfolded proteins, damaged organelles and other materials wrapped in autophagosomes not being degraded in a timely manner, interfering with the normal metabolism and function of cells, and triggering apoptotic signaling	[378]
	PARP inhibitor	Causes DNA damage, halts the cell cycle, and triggers apoptosis in cancer cells while boosting the immune system’s capacity to target tumor cells	[379, 380]
	TNF-α	Binding of TNF-α to TNFR1 induces caspase-8 activation, which ultimately leads to apoptosis	[381]
	M1 macrophages	Induces iNOS to produce large amounts of NO and increases toxic effects on tumor cells to promote apoptosis	[382]
Pyroptosis	NLRP3	The NLRP3 inflammasomes trigger caspase-1 to initiate gasdermin D-dependent pyroptosis and facilitate the release of IL-1β and IL-18	[227, 383]
	CDK inhibitors	CDK inhibitor treatment increases the levels of caspase-3 and N-terminal fragments cleaved by GSDME	[384]
	TMAO	Inducing endoplasmic reticulum stress kinase PERK triggers pyroptosis in tumor cells, which boosts CD8 T cell-mediated anti-tumor immunity against TNBC in living organisms	[385]
	GM@LR	GM@LR delivers plasmid expressing GSDME and MnCO into TNBC cells to activate caspase-3, thereby converting apoptosis to pyroptosis in 4T1 cells. In addition, Mn2+ promotes the maturation of DCs through activation of the STING signaling pathway leading to the infiltration of large numbers of cytotoxic lymphocytes	[386]
Necroptosis	Shikonin	Increased expression of RIPK3, p-RIPK3, and MLKL worked together to induce necroptosis in tumor cells, effectively triggering ICD, boosting CD8 and CD4 T cell infiltration in the tumor, and suppressing Treg cells.	[281]
	RIPK3	An alternative pathway, independent of necroapoptosis, activates PGAM5 to control NKT cell activity and enhance NKT cell-driven anti-tumor immunity	[387]
	Caspase-8	Activation of specific NK cells and CD8 T cells to improve recognition of tumor antigens	[388]
	GSDMC	GSDMC increases PARPi sensitivity in multiple cancer types by expanding memory CD8T cells in lymphoid tissues and tumors	[389]
Autophagy	PD-1/PD-L1 inhibitors	Combined administration with endostatin has a synergistic effect, leading to a decrease in the levels of IL-17 and TGF-β1, an increase in the secretion of IFN-γ, a reduction in the accumulation of MDSCs, and a reversal of the inhibition of CD8+ T cells. The expressions of vascular endothelial growth factor (VEGF), CD34, and CD31 are significantly downregulated, while apoptosis in tumor cells and autophagy mediated by the PI3K/AKT/mTOR pathway are upregulated	[390]
	HCQ	Increase the visibility of colon cancer antigens triggered by ICD inducers, and boost ICD-based anti-tumor immunity in both laboratory and live settings	[391]
	DOX	Reducing tenascin-C protein levels alongside PD-1 inhibitors elevates CD4 and CD8 tumor-infiltrating lymphocytes (TILs) and significantly boosts granzyme B release	[392]
	DMKG	This results in a heightened release of antigens and inflammatory factors, activating DCs. It can also enhance the infiltration of CD8+ T cells into the tumor area, decrease the proportion of Tregs following radiotherapy, and remodel the tumor immune environment	[393]
Ferroptosis	GPX4 inhabitors	Combined use with immune checkpoint inhibitors can promote ferroptosis	[21]
	CD8 T cell	The discharge of perforin-granzyme and Fas-FasL can trigger cell death and boost the lipid peroxidation reaction specific to ferroptosis in tumor cells	[387]
	HIFU	Induce the expression of ferroptosis-related genes such as HOX1, GST, and SQSTM to enhance drug accumulation and penetration in tumors, and stimulate effective ferroptosis-mediated anti-tumor immunity	[394]