Cellular senescence
Damaged cells can stop dividing permanently instead of dying. That protects against cancer at first, but senescent cells linger, secrete inflammatory signals, and after chemotherapy can help tumours relapse, so removing them (senolytics) is a new strategy.
Oncogene-induced and therapy-induced senescence engage p53/p21 and p16/RB to arrest the cycle; the senescence-associated secretory phenotype (SASP: IL-6, IL-8, MMPs) remodels the microenvironment, promotes inflammation, immune recruitment, and paradoxically tumour progression and treatment resistance. 'One-two punch' therapy induces senescence (e.g., CDK4/6 inhibitors, chemotherapy) then clears it with senolytics (BCL-XL/BCL-2 inhibitors, navitoclax; dasatinib+quercetin; uPAR CAR-T in mice). Senescent cells are a 2022 hallmark. Clinical proof in oncology is early; toxicity of BCL-XL inhibition (platelets) drives PROTAC approaches.
In one picture
Retired workers who refuse to leave the office. They no longer do the job, but they shout, clutter the corridors, and sometimes hire back the very people who were fired.
Diagram
top- Senescence-inducing therapy (CDK4/6 inhibitors, chemotherapy, radiation) followed by senolytics (one-two punch)
- Navitoclax and BCL-XL PROTACs; uPAR-targeted CAR-T (preclinical)
- SASP modulation with JAK inhibitors or IL-6 blockade
Notes
top- Leading programmes: Lowe (MSK) on senescence and immune clearance; Campisi legacy (Buck); Kirkland (Mayo) on senolytics; Demaria (ERIBA Groningen); Peeper (NKI) on one-two punch.