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Simple Summary Non-small cell lung cancer (NSCLC) claims almost 80% of the total lung cancer cases, with the late-stage disease having an estimated median survival time of up to five years. Patients with NSCLC benefit from traditional maximum tolerated dose (MTD) chemotherapy alone or combined with immunotherapy. However, efficacious such treatment options lead to side effects and poor patient quality of life. We show that metronomic (MTR) chemotherapy—based on the daily administration of chemotherapeutics in low, nontoxic doses—could potentially supplement MTD treatment options and indirectly prevent tumor growth leading to efficacy and less toxicity. Importantly when MTR chemotherapy is combined with an immunotherapy anti-PD1 agent, the anticipated efficacy is achieved with less toxicity, thus providing new options for the treatment of NSCLC. Abstract Pioneering studies on tumor and immune cell interactions have highlighted immune checkpoint inhibitors (ICIs) as revolutionizing interventions for the management of NSCLC, typically combined with traditional MTD chemotherapies, which usually lead to toxicities and resistance to treatment. Alternatively, MTR chemotherapy is based on the daily low dose administration of chemotherapeutics, preventing tumor growth indirectly by targeting the tumor microenvironment. The effects of MTR administration of an oral prodrug of gemcitabine (OralGem), alone or with anti-PD1, were evaluated. Relevant in vitro and in vivo models were developed to investigate the efficacy of MTR alone or with immunotherapy and the potential toxicities associated with each dosing scheme. MTR OralGem restricted tumor angiogenesis by regulating thrombospondin-1 (TSP-1) and vascular endothelial growth factor A (VEGFA) expression. MTR OralGem enhanced antitumor immunity by increasing T effector responses and cytokine release, concomitant with dampening regulatory T cell populations. Promising pharmacokinetic properties afforded minimized blood and thymus toxicity and favorable bioavailability upon MTR administration compared to MTD. The combination of MTR OralGem with immunotherapy was shown to be highly efficacious and tolerable, illuminating it as a strong candidate therapeutic scheme for the treatment of NSCLC.