Objectives: Obstructive sleep apnoea (OSA) has been associated with increased cancer risk and mortality, yet specific biomarkers for patient stratification remain lacking. This study explores the role of immune checkpoint biomarkers, soluble Galectin-9 (sGalectin-9) and TIM-3 (sTIM-3), in identifying OSA patients at higher risk of cancer-related mortality.

Methods: We conducted a multicohort, prospective observational study including 684 patients, with and without cancer, who underwent sleep studies. Plasma levels of sGalectin-9 and sTIM-3 were assessed using bead-based multiplexed assays. In vitro and ex vivo models were employed to investigate the pathogenic mechanisms underlying biomarker upregulation and their immunological impact.

Results: In severe OSA patients with melanoma or lung cancer, sGalectin-9 and sTIM-3 were associated with tumour aggressiveness and with an increased mortality risk. In the three study cohorts, biomarker levels were higher in severe OSA patients than in the other groups. In non-cancer OSA patients’ monocyte intracellular Galectin-9 and T-lymphocyte membrane-bound TIM-3 were upregulated. Experimental data revealed that intermittent hypoxia drove the expression of these biomarkers, which were positively associated with inflammatory mediators and inversely related to T-cell proliferation and infiltration. These findings underscore a mechanistic link between hypoxemia and immune suppression.

Interpretation: sGalectin-9 and sTIM-3 are promising prognostic biomarkers for medium- to long-term survival in OSA patients with melanoma or lung cancer. Their upregulation highlights a potential pathophysiological pathway connecting OSA-induced hypoxemia to cancer aggressiveness through immune modulation. Further validation could inform risk stratification and personalised therapeutic strategies.