Background: Mantle cell lymphoma (MCL) is an aggressive and incurable B-cell lymphoma. Although the role of the MCL tumor microenvironment (TME) in survival and therapeutic response has been studied, greater knowledge regarding the tumor-immune interaction is needed to develop MCL immunotherapeutic strategies. Methods: Whole exome sequencing (WES; n = 41) and RNA-seq (n = 93) were performed on fresh peripheral blood, apheresis, or biopsy MCL patient primary samples. Joint WES and RNA-seq mutation calling, expression analysis were performed by BostonGene. Results: Both tumor and TME molecular signatures were characterized based on ibrutinib response. Concurrent analysis of MCL biopsy samples with an additional previously published cohort (n = 122; Scott et al., JCO, 2017) identified 4 MCL microenvironment signatures (Nomie et al., Blood, 2019) in which the ibrutinib-resistant MCL samples primarily belonged to the “stroma-enriched” subtype (29%; 6/8 resistant, non-immune with increased stromal signature and tumor-promoting cytokines), whereas most of the ibrutinib-sensitive samples were assigned to the “immune-hot” subtype (53%, 9/9 sensitive; anti-tumor infiltration, high immune and checkpoint molecule expression with low stromal expression, Chi-square test p-value = 0.001). NOTCH1 gain-of-function mutations (25%, 3/12 resistant) in the PEST domain were found exclusively in the ibrutinib-resistant cohort associated with the microenvironment-depleted subtype. Frequent recurring inactivating mutations in the epigenetic modifier KMT2D (30%) were identified in MCL cells associated with the ‘immune-suppressed” subtype (p < 0.05). Loss-of-function mutations in epigenetic modifiers have been tied to immune evasion. PD-L1 was significantly downregulated in the ibrutinib-resistant MCL tumors (p = 0.03), indicating that targeting the PD-L1 and PD-1 immune checkpoint axis may not be beneficial. Conclusions: Ibrutinib sensitivity and resistance were defined by immune-hot and immune-cold TME portraits, respectively, suggesting that the TME has a prominent role in mediating ibrutinib response. Ibrutinib has been suggested to activate the immune TME through its off target inhibition of interleukin 2–inducible T-cell kinase (ITK). The immune activation by ibrutinib suggests that anti-tumor activity of ibrutinib may be better harnessed by combining ibrutinib with immunotherapy.