CD40/PI3K/FOXO1 axis rewiring drives microenvironment-dependent BIM silencing to sustain lymphoma growth and survival.

Both solid and hematological malignancies are recognized as complex ecosystems in which the tumor microenvironment (TME) plays a pivotal role in mediating therapeutic resistance. TME-driven modulation of BCL2-family proteins has emerged as a key determinant of treatment response in B-cell malignancies. Here, we focused on the regulation of the pro-apoptotic BH3-only protein BIM, using mantle cell lymphoma (MCL), an aggressive and incurable B-cell neoplasm, as a cellular model. Comparative analysis of circulating and lymph node samples highlighted selective BIM downregulation in malignant cells within the nodal TME, contrasting with BIM upregulation observed with normal B cells. TME-mimicking ex vivo co-culture of primary samples recapitulated this tumor-specific and microenvironment-dependent mechanism. Mechanistically, we found that BIM downregulation is driven by a lymphoma-specific CD40L-mediated rewiring of the PI3K/AKT pathway, which in turn inhibits the transcriptional activity of FOXO1. Functionally, CRISPR/Cas9-mediated deletion of BIM in MCL primary cells was sufficient to bypass their dependence on microenvironmental survival cues, leading to long-term autonomous expansion ex vivo. Moreover, BIM loss conferred broad resistance to chemotherapy and clinically relevant targeted agents. In contrast, treatment with bispecific T-cell engagers elicited robust cytotoxic responses regardless of BIM expression, underscoring the potential of immunotherapies to overcome TME-induced apoptotic resistance.