Table 2.

Hallmarks of immunosenescence: associations with tumor risk, patient prognosis, and response to immunotherapy

Hallmarks	Correlation with tumor patients	Correlation with immunotherapy response	Mechanism
Genomic instability	/	/	/
Telomere attrition	Increased risk of tumor for T cell defects [428]	/	/
Epigenetic alterations	Accelerated tumor metastasis [429]	Resistance to anti-PD-1 immunotherapy	Upregulation of E3 ubiquitin ligase BFAR in aged CD8 + T cells, activating a deubiquitinase USP39, finally inhibiting JAK2-STAT pathway, leading to a decline of tissue resident memory T (TRM) cells
	Poor survival [430]	Limited durability of anti–PD-L1 therapy	Inducing CD8 + T cell exhaustion by Asxl1, which controls the deubiquitination of histone 2 A lysine 119
Loss of proteostasis	/	/	/
Disabled autophagy	/[431]	Short progression-free survival and overall survival after PD-1 blockade therapies	Transferring mitochondria with mtDNA mutations from cancer cells into CD8+ T cells, which don’t undergo mitophagy, thus causing CD8 + T cells dysfunction
Mitochondrial defects	Accelerated tumor metastasis [277]	/	The opening of mitochondrial permeability transition pore channels to release mtDNA and lead to the mitochondria-dependent vital NETs formation in tumor-associated aged neutrophils (Naged, CXCR4 + CD62Llow)
Cellular senescence	Poor overall survival and event-free survival [432]	/	T-cell senescence and exhaustion
	Poor progonosis [433]	/	Impairing T-cell function and facilitates tumor immune evasion
	Higher mortality [434]	Less responsive to immunotherapeutic agents	T cell senescence and down-regulation of immune checkpoint genes
Hematopoietic stem cells (HSCs) myeloid bias	/	/	/
Altered intercellular communication	Poor patient survival [300]	/	T cell senescence induced by ILT4 derived from tumor cells
Chronic inflammation	Higher recurrence and poor prognosis [435]	/	Accumulation of myeloid progenitor-like cells which promotes IL-1α
Gut dysbiosis	/	/	/