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This review explores KSHV\u2019s oncogenic mechanisms, focusing on its ability to manipulate host cell signaling, evade immune detection, and promote tumorigenesis through latent and lytic viral proteins. Key oncoproteins, such as LANA, vCyc, vFLIP, and vGPCR, activate cancer hallmarks, as sustained proliferation, immune evasion, angiogenesis, and resistance to cell death, by modulating pathways such as PI3K\/AKT\/mTOR and NF-\u03baB. While histopathology and LANA staining remain diagnostic standards, emerging technologies, including advanced imaging and new molecular biomarkers, assay improved early detection. Of KSHV current therapies face challenges, especially in immunocompromised patients, highlighting the need for targeted treatments addressing viral infection. Next-generation approaches, such as CRISPR-Cas9 and therapeutic aptamers, aim to inhibit viral replication, modulate oncogenic pathways, and enhance immune responses. Current diagnosis of KS still relies primarily on histopathology and LANA immunostaining, which remain the gold standard but present important limitations, particularly in early or atypical lesions and in distinguishing latent from lytic infection. Despite advances in conventional chemotherapy and antiretroviral therapy, KSHV-associated malignancies lack virus-specific targeted treatments, and clinical outcomes remain suboptimal, especially in immunocompromised patients. By integrating emerging diagnostic biomarkers, such as viral microRNAs, with next-generation therapeutic strategies\u2014including gene editing and synthetic biology-based approaches\u2014this review highlights opportunities for precision medicine to improve disease detection, therapeutic specificity, and patient outcomes. Collectively, we provide a comprehensive framework for understanding KSHV-driven oncogenesis while outlining critical directions for future diagnostic and therapeutic innovation.<\/jats:p>","DOI":"10.1007\/s00203-025-04706-4","type":"journal-article","created":{"date-parts":[[2026,1,21]],"date-time":"2026-01-21T06:26:02Z","timestamp":1768976762000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["KSHV and cancer: understanding the oncogenic machinery for next-generation diagnostic tools and therapies"],"prefix":"10.1007","volume":"208","author":[{"given":"Jo\u00e3o Vitor Geisteira Oliveira","family":"da Silva","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eidy","family":"de Oliveira Santos","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,1,21]]},"reference":[{"issue":"10","key":"4706_CR1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1008968","volume":"16","author":"F Aalam","year":"2020","unstructured":"Aalam F, Nabiee R, Castano JR, Totonchy J (2020) Analysis of KSHV B lymphocyte lineage tropismo in human tonsil reveals efficient infection of CD138+ plasma cells. 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