Oncogenic signalling and host immunocompetency govern senescent cell clearance and systemic inflammation in a mouse model of oncogene-induced senescence

Senescence is a stress-induced program defined by permanent cell-cycle arrest and a pro-inflammatory senescence-associated secretory phenotype (SASP). Defective clearance of senescent cells promotes inflammation, tissue dysfunction, and ageing, yet determinants of their elimination remain poorly understood. Here, we model oncogene-induced senescence in the hematopoietic system by transplanting Braf V600E - or Braf ΔN -expressing hematopoietic stem and progenitor cells into recipients with distinct immune backgrounds. Braf V600E induces a stronger senescence program and more aggressive disease than Braf ΔN . Survival depends on oncogene-expressing cell burden and host immunity: immunocompetent, lower-burden mice clear oncogene-expressing cells and survive long-term, whereas higher-burden mice show checkpoint upregulation, T-cell exhaustion, and early death. NSG, Rag1KO, and lymphocyte-depleted hosts fail to clear these cells, developing sustained inflammation and bone marrow failure. Rapamycin administration attenuates senescence-associated features and improves survival. These findings identify oncogenic intensity and adaptive immune competence as coupled determinants of senescent-cell fate, with implications for chronic inflammation and senescence-targeted therapies.