Our findings provide a biological rationale to explain the superior efficacy of anti-PD1/PD-L1 therapy added to platinum-pemetrexed chemotherapy in patients with PD-L1-negative NSCLC and support pemetrexed as an ideal drug partner for chemoimmunotherapy combination regimens in advanced non-squamous NSCLC treatment. The gene discussed is PDCD1; the disease is non-small cell lung carcinoma.