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Simple Summary: Different strategies have been explored to counteract immune evasion by shifting the balance in favor of antitumor immune activation, and combination cytotoxic chemotherapies have emerged as potent immune modulators for patients with low programmed death-ligand 1 expression. This study aimed to investigate whether the addition of cyclophosphamide and adriamycin induction therapy prior to nivolumab could enhance the efficacy of immune checkpoint inhibitors in patients previously treated with non-squamous non-small-cell lung cancer with less than 10% programmed death-ligand 1 expression. Patients with a durable response to nivolumab showed higher baseline transferrin receptor protein levels. The predictive role of transferrin receptor protein as a biomarker for immune checkpoint inhibitors in non-squamous non-small-cell lung cancer with low programmed death-ligand 1 expression was validated in an independent cohort. This study aimed to investigate whether cyclophosphamide (C) and adriamycin (A) induction therapy (IT) prior to nivolumab could enhance the efficacy of nivolumab in previously treated patients with non-squamous (NSQ) non-small-cell lung cancer (NSCLC) with less than 10% programmed death-ligand 1 (PD-L1) expression. Twenty-two enrolled patients received four cycles of CA-IT every 3 weeks. Nivolumab was given 360 mg every 3 weeks from the second cycle and 480 mg every 4 weeks after four cycles of CA-IT. The median progression-free survival (PFS) and overall survival (OS) were 2.4 months and 11.6 months, respectively. Fluorescence-activated cell sorting revealed the lowest ratio of myeloid-derived suppressor cells (MDSCs) to CD8+T-cells in the responders. Proteomic analysis identified a consistent upregulation of extracellular matrix-receptor interactions and phagosome pathways in the responders. Among the differentially expressed proteins, the transferrin receptor protein (TFRC) was higher in the responders before treatment (fold change > 1.2). TFRC validation with an independent cohort showed the prognostic significance of either OS or PFS in patients with low PD-L1 expression. In summary, CA-IT did not improve nivolumab efficacy in NSQ-NSCLCs with low PD-L1 expression; however, it induced decreasing MDSC, resulting in a durable response. Higher baseline TFRC levels predicted a favorable response to nivolumab in NSCLC with low PD-L1 expression. [ABSTRACT FROM AUTHOR]