RGS5 (regulator of G protein signaling 5) functions as a negative regulator of G protein-coupled receptor signaling by increasing the GTPase activity of G protein alpha subunits, driving them into their inactive GDP-bound form 1. In cancer contexts, RGS5 expression defines distinct cellular populations with critical roles in tumor progression and therapeutic resistance. RGS5+ cancer-associated fibroblasts (CAFs) represent a clinically significant population that promotes immunosuppressive tumor microenvironments across multiple cancer types, including pancreatic ductal adenocarcinoma liver metastases 2, breast cancer 3, skin cancers 4, and epithelial ovarian cancer 5. These RGS5+ CAFs facilitate metastasis through various mechanisms, including support of tumor-endothelial adhesion and transendothelial migration 6, and contribute to drug resistance by functioning as 'metabolic sinks' that accept damaged mitochondria from cancer cells via tunneling nanotubes 7. RGS5 expression in endothelial cells responds to oxidative stress and promotes lymph node metastasis 6. The protein also plays a role in vascular normalization, where it regulates vessel maturation alongside other factors in anti-VEGF therapy responses 1. Clinically, RGS5+ populations correlate with poor prognosis and treatment resistance, making them potential therapeutic targets for combination therapies.