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Here, we show that sialic acid-binding immunoglobulin-like receptor 15 (Siglec-15), an immunosuppressive membrane protein, is upregulated and mediates SHH-MB growth through its translocation to the lysosomal membrane. We found that SHH-MB cells use the cation-independent mannose 6-phosphate receptor (CI-MPR) to transport Siglec-15 from the trans-Golgi network (TGN) to lysosomes, where Siglec-15 induces lysosomal Ca2+ release by interacting with mucolipin TRP cation channel 1 (TRPML1), leading to the nuclear translocation of the transcription factor EB (TFEB). Blockade of Siglec-15, TRPML1, or TFEB hinders SHH-MB growth in vitro and in vivo. Importantly, aryl hydrocarbon receptor (AhR), a cytoplasmic transcription factor, upregulates Siglec-15 expression. AhR inhibition by CH-223191 or StemRegenin 1 (SR1) achieved therapeutic efficacy against orthotopic SHH-MB xenografts in mice. These findings reveal an essential role for the AhR-Siglec-15 axis in SHH-MB development, providing a potential strategy for SHH-MB treatment.<\/jats:p>","DOI":"10.1093\/procel\/pwaf100","type":"journal-article","created":{"date-parts":[[2025,11,14]],"date-time":"2025-11-14T13:01:51Z","timestamp":1763125311000},"page":"438-451","source":"Crossref","is-referenced-by-count":0,"title":["AhR-Siglec-15 axis regulates lysosomal Ca2+ release for sonic hedgehog medulloblastoma growth via TRPML1"],"prefix":"10.1093","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7407-7065","authenticated-orcid":false,"given":"Zhenfeng","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Immunology, State Key Laboratory of Common Mechanism Research for Major Diseases, Institute of Basic Medical Sciences and School of Basic Medicine, Chinese Academy of Medical Sciences (CAMS) and Peking Union Medical College , Beijing 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