Senescent fibroblasts interfere with the tumor immune response in humanized models by inducing neutrophil extracellular traps

ABSTRACT Neutrophils are known to promote tumor progression and metastasis, in part through the release of extracellular traps (NETs), a phenomenon associated with poor prognosis in patients. Here, we demonstrate that senescent fibroblasts, via their senescence-associated secretory phenotype (SASP), promote the recruitment of CD33 + myeloid cells and impair the tumor immune response in an orthotopic humanized mouse lung cancer model. Mechanistically, we found that therapy-induced senescence triggers the formation of NETs, which interfere with immune cell infiltration in tumor spheroids. This phenotype was reversible upon treatment with DNAse I or Reparixin, an inhibitor of the action of CXCL8/IL-8 and CXCL1/GRO1, two key SASP factors. Furthermore, we show that senescence-induced NETs favor lung metastasis in a humanized mouse model, a phenotype that was inhibited by DNase I treatment. Our findings provide critical insights into the complex interplay between cellular senescence, NETosis, and the tumor immune response, highlighting another mechanism by which senotherapies can improve cancer treatments.