CAND1 Promotes Lung Cancer Tumorigenesis by Mitochondrial DNA Release mediated Neutrophil Infiltration

CAND1, a conserved regulator of cullin-RING ubiquitin ligases, has been well characterized in protein homeostasis, but its functional role in lung adenocarcinoma (LUAD) remains largely unknown.

Bioinformatic and clinical analyses assessed CAND1 expression and prognostic significance. Multiplex immunofluorescence and flow cytometry evaluated neutrophil infiltration and activation. Transwell assays and flow cytometry assessed neutrophil migration and NETosis. CAND1-modulated LUAD cells were used to examine mitochondrial remodeling, mtDNA release, cGAS-STING/NF-κB signaling, and chemokine expression, and Xenograft models to assess tumor growth and neutrophil involvement in vivo.

CAND1 is upregulated across multiple solid tumors, and its elevated expression is associated with poor prognosis in LUAD patients, as validated by public datasets and clinical cohort. CAND1 expression correlates with increased neutrophil infiltration and activation, which is further validated by co-culture experiments with isolated neutrophils and CAND1-overexpressing tumor cells. Mechanistically, CAND1 promotes mitophagy, leading to mtDNA release and sustained activation of the cGAS-STING/NF-κB signaling axis. STING knockdown markedly attenuated CAND1-associated neutrophil migration and reduced the expression of neutrophil-recruiting chemokines, including CCL5, CCL7, CXCL1, CXCL5, and CXCL8. In vivo, CAND1 overexpression accelerates xenograft tumor growth and enhances intratumoral neutrophil infiltration, while neutrophil depletion partially attenuates CAND1-associated tumor growth, supporting a functional contribution of neutrophils to CAND1-associated tumor progression.

CAND1 links mitophagy to immune remodeling through cGAS-STING activation and subsequent chemokine-mediated neutrophil recruitment, establishing it as a key regulator of LUAD progression.