Active HNSCC smokers display an immunosuppressed TIME because of direct T-cell inhibition by CSE [33], the suppression of T-cell chemotaxis, and a consequent reduction in T-cell tumor infiltration [11]; moreover, the IFNα and IFNγ axis is downregulated, which, among other effects, leads to low PD-L1 and PD-L2 expression with a low response to immune checkpoint inhibitors [107]. Here, PDCD1LG2 is linked to head and neck squamous cell carcinoma.