SNHG18 deficiency reprograms arginine metabolism to foster an immunosuppressive microenvironment in prostate cancer bone metastasis.

Advanced prostate cancer (PCa) frequently metastasizes to bone, where the immunosuppressive tumor microenvironment (TME) limits immune checkpoint blockade (ICB) efficacy. Nevertheless, the molecular mechanisms underlying this immunosuppressive bone TME and bone metastasis (BM) are not yet fully understood. Analysis of clinical PCa samples, employing in situ hybridization, RT-qPCR, and bioinformatics, demonstrated a progressive downregulation of lncRNA SNHG18 throughout PCa progression, with the lowest expression levels observed in BM associated with poor prognosis. We demonstrate that the downregulation of SNHG18 contributes to castration-resistant prostate cancer (CRPC) and BM development by utilizing an androgen-independent Myc-CaP subline, derived from Androgen receptor positive (AR+) Myc-CaP cells through chronic steroid deprivation, alongside in vitro and in vivo models. SNHG18 alters the bone microenvironment through the reprogramming of arginine metabolism. Deficiency of SNHG18 resulted in the upregulation of ARG2 and NOS2, which caused arginine depletion, enhanced infiltration of immunosuppressive cells, and compromised effector T-cell function. Mechanistically, SNHG18 bound to YBX1 and recruited TRIM21 to induce YBX1 degradation, thereby inhibiting YBX1-mediated transcriptional activation of NOS2 and ARG2. Therapeutically, SNHG18 overexpression enhanced anti-PD-1 therapy efficacy in murine BM models. Consequently, SNHG18 deficiency fosters an immunosuppressive TME and promotes PCa BM. SNHG18 expression may serve as a predictive biomarker for ICB response, offering a novel strategy to overcome immunotherapy resistance in PCa BM.