Therapy-Induced Cellular Senescence in Non-Hodgkin Lymphomas, with Emphasis on Aggressive B-Cell Subtypes: Molecular Mechanisms and Emerging Drug Targets.

INTRODUCTION/

BACKGROUND

Therapy-Induced Senescence (TIS) is increasingly recognized as a clinically relevant outcome of anticancer therapy, particularly after sublethal genotoxic stress. In Non-Hodgkin Lymphomas (NHL), TIS may coexist with apoptosis and contribute to treatment heterogeneity by enabling the long-term survival of dam-aged but viable tumor cells. The aim of this article is to synthesize the core molecular mechanisms of TIS in NHL, and to highlight druggable senolytic and senomorphic strate gies that may improve disease control and reduce the risk of relapse.

MATERIAL AND

METHODS

A narrative review was conducted using mechanistic and translational literature addressing DNA Damage Response (DDR) signaling, p53-p21 and p16^INK4a^-RB checkpoint pathways, Senescence-Associated Secretory Phenotype (SASP), epigenetic remodeling, senescence escape, stemness acquisition, and therapeutic targeting of senescent tumor cells. Searches were performed in PubMed / MEDLINE, Scopus, and Google Scholar using combinations of the terms "therapy-induced senescence", "cellular senescence", "SASP", "senolytic", "senomorphic", and "senescence escape". Priority was given to studies published between 2010 and 2026, while older land-mark studies were included when mechanistically essential.

RESULTS

TIS is initiated by persistent DDR signaling (ATM/ATR→CHK1/CHK2) with downstream activation of p53-p21 and/or p16^INK4a^-RB pathways, resulting in stable growth arrest. Senescent lymphoma cells may acquire a SASP that remodels the tumor microenvironment and modulates immune responses. Epigenetic reprogramming (e.g., SAHF formation, H3K9me3 dynamics, lamin B1 loss) supports phenotypic plasticity and may enable escape from senescence with stem-like features, contributing to residual dis-ease persistence and relapse biology.

DISCUSSION: Therapeutically, senolytic approaches (e.g., BH3 mimetics, BCL-2/BCL-xL antagonists) and senomorphic strategies (targeting SASP regulators such as NF-κB, JAK/STAT, and mTOR) represent potentially actionable therapeutic approaches. Emerging senolytic Chimeric Antigen Receptor T-cell (CAR-T cell) strategies targeting senescence-associated surface programs, such as uPAR, further expand the therapeutic landscape, although these approaches remain at a preclinical stage at the time of writing this review.

CONCLUSION

In lymphomas, TIS is a dynamic stress-adaptation state that can support persistence and relapse. Rational integration of senescence biomarkers, timing-based therapies, and targeted senolytic/senomorphic interventions may enhance long-term treatment efficacy; however, most senescence-targeted strategies remain investigational and require lymphoma-specific clinical validation.