Future Perspectives in Senescence-Based Therapies for Head and Neck Cancer

Abstract

Cellular senescence is a complex physiological process in which cells permanently stop dividing and enter a stable state of cell-cycle arrest. This mechanism is typically triggered by various stressors, such as DNA damage, oxidative stress, telomere shortening, and oncogene activation. Senescent cells remain metabolically active and significantly influence their microenvironment through the senescence-associated secretory phenotype (SASP), which includes the secretion of inflammatory cytokines, growth factors, and proteases. While cellular senescence serves as a crucial tumor-suppressive mechanism by preventing the proliferation of damaged or potentially cancerous cells, it also plays a paradoxical role by promoting chronic inflammation, tissue dysfunction, and potentially oncogenesis. Therefore, understanding the regulation and impact of cellular senescence is vital for developing therapeutic interventions that leverage its benefits while minimizing adverse outcomes. In this review, we provide an overview of the current understanding of cellular senescence in cancer biology and discuss the emerging field of senescence-targeted therapies. We focus specifically on the role of senescence in head and neck cancers, examining the potential of induced senescence therapy to mitigate the progression of these tumors. This review aims to correlate the dual nature of senescence with innovative therapeutic strategies, highlighting its promise and challenges in improving treatment outcomes for HNC patients.

Keywords: HNSCC; biomarkers; cancer therapy; cellular senescence; chromatin organization; epigenetic regulation; therapy-induced senescence.

Figure 1

Schematic illustration of the nature of cellular senescence in cancer: Cellular senescence suppresses tumor growth by arresting proliferation, yet persistent senescent cells can drive cancer progression via chronic SASP secretion and rare escape mechanisms like EMT or neosis [22,23]. This figure was generated using Napkin AI.

Figure 2

Comparative overview of key senescence biomarkers: This table summarizes major senescence biomarkers, including SA-β-Gal, SAPA, DNA damage, SUV39H1, and Lamin B1. Each marker reflects distinct mechanisms, such as lysosomal expansion, persistent cell-cycle arrest, DNA damage response, and epigenetic or nuclear changes [15,16,26,27,28,29,30,31,32,33,34,35,36,37]. This figure was generated using Napkin AI.

Figure 3

This chart illustrates the paradoxical role of the senescence-associated secretory phenotype in cancer. The SASP can suppress tumor development by enhancing immune-mediated clearance of premalignant cells and promoting tissue repair. Conversely, it can also promote tumorigenesis by inducing chronic inflammation and DNA damage in neighboring cells, and by supporting cancer-related processes like angiogenesis and EMT. Key SASP mediators drive these opposing effects, depending on the cellular context. This figure was generated using Napkin AI.

Figure 4

This diagram outlines therapies that induce or enhance senescence in head and neck cancer. Approaches include cytotoxic agents, senolytic drugs, oxidative stress modulation, CDK4/6 and bromodomain inhibitors, and NNMT inhibition. Together, these strategies aim to suppress tumor growth by promoting or clearing senescent cancer cells. This figure was generated using Napkin AI.