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Background The phase 3 ZUMA-7 randomized trial in 2nd-line relapse/refractory (r/r) large B-cell lymphoma (LBCL) demonstrated transformative superior outcome for patients receiving anti-CD19 CAR-T cell therapy axicabtagene ciloleucel (axi-cel) versus historical standard of care. However, about 60% of patients with r/r LBCL experience disease progression following axi-cel treatment. Classic prognostic factors, including cell-of-origin molecular subtype, did not explain axi-cel differential outcomes. Here, a multi-omics analysis was leveraged to identify mechanisms of CAR-T cell therapy resistance.Methods RNA-sequencing was performed on pre-treatment ZUMA-7 tumor biopsies (n = 245).139 pre-defined gene expression signatures (GES) capturing the density and functional orientation of immune cells, as well as cancer-immune interactions and oncogenic signaling were used to characterize LBCL immune subtypes. Olink assessment of ~3000 proteins in pretreatment plasma samples (n = 103) was correlated to the subtypes and outcomes. Immunohistochemistry data, product T cell phenotypes, and other prognostic attributes (e.g. LDH, HGBL) were compared across subtypes.Results Consensus clustering of tumor biopsies using 51 GES selected after co-linearity exclusion revealed seven distinct LBCL subtypes with differential Event Free Survival (EFS; P < 0.05) to CAR-T cell therapy (axi-cel). High CD19 protein and/or gene expression, high B-cell GES, high T cells and/or antigen presenting cells were characteristic of three clusters presenting the best EFS with axi-cel (‘favorable’ tumor microenvironments (TMEs), Clusters 1-3). Two clusters with the worst EFS were characterized by elevated IFN signaling, infiltration of exhausted CD8 T cells, myeloid (eg. M2) suppression (cluster 6) and high stromal/TGF-beta signaling (cluster 7). Anti-apoptotic features and/or lack of immune cell infiltration were characteristics of two clusters (clusters 4-5) with intermediate EFS. A high proportion of naïve-like T cells (CCR7 + CD45RA+) in the product, a feature previously linked to durable response, did not associate with prolonged EFS in patients with unfavorable TMEs. MARCO (Macrophage receptor with collagenous structure) and IL-8 (interleukin-8) concentrations in plasma were among the top analytes associated with prolonged EFS (P < 0.0001) in intermediate and unfavorable TMEs. MARCO plasma level correlated with tumor MARCO gene expression and interferon signatures. MARCO gene expression and myeloid signatures were elevated in cluster 6.Conclusions We identified interferon-associated T cell exhaustion, myeloid suppression, stromal/TGF-beta signaling, anti-apoptotic features and lack of antigen presentation as determinants of resistance to CAR-T cell therapy. These pathways may be targeted to counter an immune-suppressive TME. MARCO and IL-8 plasma levels emerged as potential predictive biomarkers of efficacy.