Senescence-independent SASP drives tumor-macrophage inflammatory cascade and therapeutic resistance in HNSCC

Head and neck squamous cell carcinoma (HNSCC) exhibits profound resistance to chemoradiotherapy and immune checkpoint inhibition, which is closely associated with therapy-induced cellular senescence. However, the regulatory mechanism of the senescence-independent senescence-associated secretory phenotype (SASP) driven by double-stranded RNA (dsRNA)-mediated innate immune activation after chemoradiotherapy remains largely unknown. The dsRNA mimic polyinosinic-polycytidylic acid [poly(I:C)] was used to stimulate CAL27 cells, with chloroquine (CQ) intervention to inhibit autophagy. Integrated transcriptomic analysis, in vitro functional assays and clinical specimen validation were performed to explore the regulation, transcellular cascade and prognostic value of senescence-independent SASP. dsRNA-mediated innate immune stimulation triggered NF-κB-dependent senescence-independent SASP in an autophagy-dependent manner without inducing proliferative arrest or classic senescence marker expression. CXCL1 was identified as a candidate key mediator of this SASP subtype. Furthermore, senescence-independent SASP initiates an IL-6-mediated transcellular inflammatory cascade to activate SASP in tumor-associated macrophages, remodeling the immunosuppressive tumor microenvironment. Autophagy inhibition effectively suppressed this SASP, reduced IL-6 secretion and disrupted the tumor-macrophage inflammatory loop. Clinically, the TLR3-autophagy-NF-κB-IL-6 signature was validated as a reliable prognostic biomarker for oral squamous cell carcinoma (HNSCC). This study reveals a novel autophagy-NF-κB-IL-6 axis governing senescence-independent SASP and the downstream inflammatory cascade in HNSCC, representing a promising therapeutic strategy to improve chemoradiotherapy plus immunotherapy efficacy.