In summary, we demonstrated that a poorly or highly proliferative potential in the tumor microenvironment is associated with resistance to ICI-based immunotherapy amongst NSCLC patients, and that assessing the expression levels of ten proliferation-related genes by RNA-seq in diagnostic biopsies stands out as a promising strategy for improving clinical decision making based on PD-L1 expression only. Here, CD274 is linked to non-small cell lung carcinoma.