Senolytics for cancer treatment: complexities and opportunities

There is currently growing interest in targeting senescent tumor cells as a strategy for improving the efficacy of cancer therapy. Despite the promise of this strategy, a number of limitations have emerged relating to the utility of senescence-eliminating agents, collectively termed senolytics. First, these compounds show different outcomes in aging and tumor cell models. Second, they exhibit variable efficacy in eliminating senescent tumor cells based on tumor background. Third, efficacious agents do not necessarily eliminate the risk of proliferative recovery that could reflect disease recurrence. Fourth, several of the compounds that demonstrate the highest efficacy against senescent tumor cells are associated with established or potential adverse effects that would limit their translation.

Here, we provide an overview of the advantages and disadvantages of established senolytics and explore the potential for newly identified agents strictly tested in tumor cell models.

Senolytic translation is constrained by Therapy-induced Senescence (TIS) heterogeneity generating resistant subpopulations, potential proliferative recovery, senolytic-associated adverse effects, risk for targeting beneficial senescent cells, and absence of validated clinical trial designs. Emerging immune-based strategies nanovaccines, nano-antigen-presenting machinery, and CAR-T platforms offer more selective alternatives, but require validated preclinical and clinical testing for further implementation.