Neutral sphingomyelinase 2 (nSMase2) with SMPD3 encoding catalyzes the breakdown of sphingolipid to produce the anti-tumor ceramide linked to apoptosis, growth arrest and chemotherapeutic response (158), accumulates TH1 polarization and CD8+ TILs with increased IFN-γ and chemokine C-X-C motif ligand 9 (CXCL9), and even increases anti-PD-1 efficacy in murine models of melanoma and breast cancer (159). Here, SMPD3 is linked to breast cancer.