Lung and colorectal cancer are among the top three most deadly malignancies and together they account for ~32% of all cancer-related fatalities. Although anti-cancer immunotherapy using PD-1 and CTLA-4 blocking antibodies shows prominent activity and has been approved for use in multiple tumors, most patients show treatment resistance and there are striking differences in the clinical activity across tumor types. Currently, the determinants for treatment sensitivity/resistance and the difference in the role of dominant immune evasion pathways across cancers are uncertain. To substantially reduce lung and colorectal cancer mortality, it is imperative to: i) Identify novel biomarkers for optimal selection of patients for treatment; ii) Uncover immunotherapy targets beyond the PD-1/CTLA-4 pathways that may serve to treat patients with refractory tumors; and iii) Reveal the role of immunity during tumor progression to design early therapeutic interventions. Recent studies from our group identified the IL-8/CXCR1/CXCR2 pathway as a strong determinant for negative immune modulation and therapeutic resistance to immune checkpoint blockers. The immune suppressive effects of the IL-8 pathway involve increased neutrophils in the tumor niche and local development of neutrophil extracellular traps (NETs). We hypothesize that the deleterious effects of the IL-8 pathway in the tumor immune microenvironment are promoted by local metabolic suppression. We anticipate these responses to be different in tumors with distinct immune properties and sensitivity to immune checkpoint blockers such as lung and colorectal cancer; and during early stages of tumor development. In this project and through 3 complementary aims, we will leverage our expertise in cancer immunobiology and translational research to: i) Determine the metabolic/immune context and biomarker value of the IL-8 pathway and myeloid-cell responses in cancer; ii) Analyze the mechanisms and role of IL-8 induced NET formation as negative immunomodulatory event in human malignancies; and iii) Examine the role of the IL-8 pathway and immune contexture in carcinogenesis and early cancer progression. The results from this work will accelerate translation of research concepts into the clinic for establishment of novel biomarkers, support interpretation of clinical trials and design optimal treatment modalities for early-stage and advanced tumors.