Virus–Immune Signatures Reveal Distinct Clinical Phenotypes and Predict Prognosis in Patients with Kaposi's Sarcoma

Background Kaposi's sarcoma (KS) is a Kaposi's sarcoma-associated herpesvirus(KSHV)-driven multicentric malignancy that demonstrates significant clinical heterogeneity. Current etiology-based classifications fail to capture the underlying biological drivers, limiting prognostic accuracy and personalized management. Objective To define biology-driven phenotypes of KS through integrated analysis of KSHV viral load and immune parameters and to evaluate their clinical relevance and prognostic value. Methods This retrospective study included patients with KS. Unsupervised clustering was performed using KSHV viral load, four cytokines and four lymphocyte subsets levels. Results A total of 142 patients were included. Cluster analysis identified three distinct patient subgroups as follows: (1) Cluster 1(‘High-Viral Immune-Activated’, n=38); (2) Cluster 2 (‘Heterogeneous’ , n=82); (3) Cluster 3 (‘High-Viral Immune-Exhausted’ , n=22). Cluster 3 was characterized by high KSHV viral load, severe CD4T cell depletion, and was enriched for AIDS-KS (86.4%). It was strongly associated with more severe disease (Krigel grade ≥3: 63.6%, p <0.001), poor treatment response (SD/PD: 90.9%, p =0.007), and significantly worse overall survival (log-rank p<0.0001). Multivariable analysis confirmed Cluster 3 as an independent predictor of mortality(HR for Cluster 2 vs . 3 = 0.339, 95% CI: 0.082–0.379, p =0.046). GBTM revealed that all Cluster 3 patients followed a 'Persistently High' viral trajectory during treatment, explaining the treatment resistance. The prognostic nomogram integrating the virus-immune cluster demonstrated good discrimination. Conclusion We propose a biology-driven subtyping of KS into three distinct entities based on integrated virus-immune profiles. The 'High-Viral Immune-Exhausted' phenotype identifies patients with aggressive, treatment-refractory disease and poor survival.