Targeting Senescence as a Therapeutic Opportunity for Triple-Negative Breast Cancer

Triple-negative breast cancer (TNBC) is associated with an elevated risk of recurrence and poor prognosis. Historically, only chemotherapy was available as systemic treatment, but immuno-therapy and targeted therapies currently offer prolonged benefits. TNBC is a group of diseases with heterogeneous treatment sensi-tivity, and resistance is inevitable and early for a large proportion of the intrinsic subtypes. Although senescence induction by anticancer therapy offers an immediate favorable clinical outcome once the rate of tumor progression reduces, these cells are commonly dysfunctional and metabolically active, culminating in treatment -resistant repopulation associated with worse prognosis. This het-erogeneous response can also occur without therapeutic pressure in response to damage or oncogenic stress, playing a relevant role in the carcinogenesis. Remarkably, there is preclinical and explor-atory clinical evidence to support a relevant role of senescence in treatment resistance. Therefore, targeting senescent cells has been a scientific effort in many malignant tumors using a variety of targets and strategies, including increasing proapoptotic and decreasing antiapoptotic stimuli. Despite promising results, there are some challenges to applying this technology, including the best schedule of combination, assessment of senescence, specific vulner-abilities, and the best clinical scenarios. This review provides an overview of senescence in TNBC with a focus on future-proofing senotherapy strategies.

Automated summary

Triple-negative breast cancer (TNBC) is associated with a high risk of recurrence and poor prognosis. Previous systemic treatment options were limited to chemotherapy, but now immunotherapy and targeted therapies provide longer-lasting benefits. Treatment resistance due to heterogeneous response is a challenge in TNBC, and induction of senescence by anticancer therapy may lead to dysfunctional and metabolically active cells that foster treatment-resistant repopulation. Targeting senescent cells has shown promise in overcoming resistance, but there are challenges in terms of combination schedules, senescence assessment, specific vulnerabilities, and clinical applicability. This review provides an overview of senescence in TNBC and explores future strategies in senotherapy.