LRRC15 is a leucine-rich repeat membrane protein with dual roles in viral antagonism and tumor stromal biology. In viral infection, LRRC15 modulates SARS-CoV-2 infectivity by sequestering virions and antagonizing viral infection of ACE2+ cells in trans without serving as a direct entry receptor 1. In cancer, LRRC15 functions primarily as a marker of immunosuppressive cancer-associated fibroblasts (CAFs). TGFβ signaling drives LRRC15+ myofibroblast development from universal fibroblasts 23, generating a CAF population that dictates tumor-fibroblast composition and directly suppresses CD8+ T cell effector function, limiting checkpoint blockade efficacy 2. LRRC15+ fibroblasts are enriched in immunosuppressive tumor microenvironments across multiple cancer types and correlate with poor immunotherapy response 34. Beyond stromal expression, LRRC15 is expressed on mesenchymal cancer cells (sarcoma, melanoma, glioblastoma) and promotes metastatic dissemination via β1-integrin/FAK signaling in ovarian cancer 56. Clinically, LRRC15 serves as a predictive biomarker for immunotherapy resistance and represents a validated therapeutic target; the antibody-drug conjugate ABBV-085 demonstrates antitumor activity in osteosarcoma and undifferentiated pleomorphic sarcoma 78.