Fatty acid synthesis therapy-induced senescence (FASTIS) in cancer cells.

Therapy-induced senescence (TIS) in cancer cells can be triggered by radiotherapy, chemotherapy, and certain targeted therapeutics. Here, we demonstrate that a new form of TIS, termed fatty acid synthesis therapy-induced senescence (FASTIS), can be induced by pharmacologically targeting de novo lipogenesis. Cancer cells can evade the anti-proliferative effects of clinically relevant inhibitors of core lipogenic enzymes, such as acetyl-CoA carboxylase (ACC) and fatty acid synthase (FASN), by entering in a senescence-like state. FASTIS cancer cells acquire the classical senescence hallmarks, such as cytomorphological remodeling, increased senescence-associated beta-galatosidase (SA-β-gal) activity, activation of cell cycle arrest markers, and hypersensitivity to IFNγ-induced activation of the immune checkpoint PD-L1. mRNA sequencing reveals an FASTIS-associated transcriptomic profile that overlaps between ACC and FASN inhibitors yet differs significantly from that of other mechanistically diverse TIS inducers, including bleomycin, alisertib, doxorubicin, and palbociclib. The FASTIS-encoding transcriptome is characterized by the activation of cholesterol- and acetyl-CoA-related lipogenic pathways, as well as cell-intrinsic innate immune responses. This profile is characterized as highly senescent (≥0.95) by the machine learning-based senescence predictor SENCAN. Mapping the metabolome and lipidome in FASTIS cells reveals a significant sterol lipid enrichment, including substantial increases in intracellular cholesterol levels. Pharmacological blockade of cholesterol synthesis or promotion of lysosomal cholesterol accumulation, prevents or potentiates the occurrence of SA-β-gal+ FASTIS cells, respectively. Cytokine arrays and miR-146a reporter-based screens revealed that the FASTIS-associated secretory phenotype (FASASP) is highly enriched in immunomodulatory factors but not in inflammatory components. FASTIS cancer cells exhibit an increased overall level of mitochondrial priming, making them highly susceptible to targeted senolysis by BCL-xL-targeting BH3 mimetics and cytokine-activated T cells. The FASTIS phenomenon is a therapeutic outcome through which cancer cells adapt to survive clinical-grade lipogenesis inhibitors. The cholesterol-addicted FASTIS fate can be rationally exploited as a collateral sensitivity in "one-two punch" senogenic-(immuno)senolytic strategies.