The clinical translation of small-molecule STAT3 inhibitors faces challenges due to off-target effects on nonmalignant cells, such as the reduced antitumor activity of CD8+ T cells.49 To overcome this challenge, we utilized TLR9-specific antisense oligonucleotides recently developed for targeting myeloid suppressor cells in the microenvironment of solid tumors, such as prostate, renal or head and neck cancers.33,35,50 For targeted STAT3 downregulation in TANs, a STAT3 antisense molecule tagged with CpG (a TLR9 ligand) was generated. The gene discussed is CD8A; the disease is head and neck cancer.