Interestingly, apart from directly aiming at tumor cells, suppressing Hh signaling could also reconfigure the TIME to be active [55]. Tumor-derived sonic hedgehog (SHH), the hg signaling ligand, acts at TAM to drive M2 polarization which inhibits CD8+ T cell recruitment to the TIME and promotes tumor progression [60]. The gene discussed is GDF15; the disease is neoplasm.