The crosstalk between senescence, tumor, and immunity: molecular mechanism and therapeutic opportunities

Abstract

Cellular senescence is characterized by a stable cell cycle arrest and a hypersecretory, proinflammatory phenotype in response to various stress stimuli. Traditionally, this state has been viewed as a tumor-suppressing mechanism that prevents the proliferation of damaged cells while activating the immune response for their clearance. However, senescence is increasingly recognized as a contributing factor to tumor progression. This dual role necessitates a careful evaluation of the beneficial and detrimental aspects of senescence within the tumor microenvironment (TME). Specifically, senescent cells display a unique senescence-associated secretory phenotype that releases a diverse array of soluble factors affecting the TME. Furthermore, the impact of senescence on tumor-immune interaction is complex and often underappreciated. Senescent immune cells create an immunosuppressive TME favoring tumor progression. In contrast, senescent tumor cells could promote a transition from immune evasion to clearance. Given these intricate dynamics, therapies targeting senescence hold promise for advancing antitumor strategies. This review aims to summarize the dual effects of senescence on tumor progression, explore its influence on tumor-immune interactions, and discuss potential therapeutic strategies, alongside challenges and future directions. Understanding how senescence regulates antitumor immunity, along with new therapeutic interventions, is essential for managing tumor cell senescence and remodeling the immune microenvironment.

Keywords: SASP; cancer treatment; cellular senescence; immunity; tumor microenvironment; tumor progression.

FIGURE 1

Effects of cellular senescence in tumor cell suppression and promotion. (A) SASP factors suppress tumor by reinforcing cell cycle arrest or enhancing immune surveillance. IL‐6 and IL‐8 can strengthen cellular senescence in an autocrine manner, while interleukins can spread senescence to adjacent cancer cells in a paracrine manner. Some cytokines, such as IL‐6, IL‐8, CXCL1, and CCL2, could recruit natural killer (NK) cell, T cell, neutrophils, and macrophages contributing to immune surveillance. (B) In the TME, various SASP factors are linked to cancer proliferation, migration, invasion, and metastasis, consequently enhancing the malignant capacities of cancer cell population. Also, several SASP factors could modulate the TME by prompting angiogenesis and preventing the antitumor functions of immune effectors. ECM, extracellular matrix; EMT, epithelial‐to‐mesenchymal transition; MDSC, myeloid‐derived suppressor cells; MMP, matrix metalloproteinase; SASP, senescence‐associated secretory phenotype; VEGF, vascular endothelial growth factor.

FIGURE 2

T cell senescence‐related signaling pathways. Hypoxia‐driven cAMP can be transferred to T cells, inducing DNA damage via PKA–CREB pathway activation. Glucose competition could trigger ATM‐related DNA damage, induce ERK1/2 and P38 pathways, and interacts with STAT1/3, leading to T‐cell senescence. The downregulation of TCR signaling can trigger the activation of P38 pathway while inhibiting the PI3K‐AKT–mTOR signaling pathway. This leads to the inactivation of autophagy and the induction of mitochondrial dysfunction in senescent T cells. The cGAS–STING pathway also modulates the secretion of SASP factors. Treg cell, regulatory T cell; TCR, T cell receptor; SASP, senescence‐associated secretory phenotype.

FIGURE 3

Major changes in different immune cell subsets during immunosenescence. The senescence of the immune system indicates aging of various immune cell types. Prominent characteristics of immune cell senescence include a decline in immune function and an increase in the secretion of inflammatory factors. The number of naïve T and B cell is decreased, while the quantity of memory T and B cell is increased. The antigen presentation and phagocytic functions of dendritic cells are impaired. The functionality of NK cells is impaired, while the number and activity of MDSCs and macrophages are increased. MDSCs, myeloid‐derived suppressor cells; NK cell, natural killer cell.

FIGURE 4

Senescent tumor cells regulate the antitumor immune response. Senescent tumor cells prompt a switch from immune evasion to immune clearance by remodeling their surface proteome, which leads to the following consequences: (1) enhanced IFN‐γ signaling, (2) upregulated MHC‐I levels, and (3) altered immunopeptidome expression. Meanwhile, this robust antigen presentation machinery increases the engagement of effector immune cells, such as effector T cells, dendritic cells, and macrophages. These cells work together to clear tumor cells from the host. IFN‐γ, interferon‐γ; MHC‐I, major histocompatibility complex‐I.