Myeloid CD93 binds to CD69 on T cells to drive resistance to T-cell engager therapy

Resistance remains a major barrier to durable therapeutic efficacy of bispecific T-cell engagers (TCE) across both hematologic and solid malignancies. Beyond tumor- and T cell-intrinsic determinants of resistance, accumulating evidence indicates that the extrinsic tumor immune microenvironment (TIME) can critically constrain therapeutic efficacy. However, whether tumor-infiltrating myeloid populations directly suppress TCE-engaged T cells through contact-dependent cell–cell interactions remains incompletely defined. Here, we profiled the TIME of relapsed or refractory B-cell non-Hodgkin lymphoma (B-NHL) patients before and after receiving TCE therapy and observed a marked post-treatment enrichment of immunosuppressive tumor-infiltrating myeloid cells (TIMCs). Mechanistically, TCE-activated T cells recruited TIMCs via CCR5-dependent chemotaxis and induced BTK signaling in TIMCs, leading to upregulation of the downstream effector CD93, which in turn suppressed T-cell proliferation and activation. We further identified CD69 as a functional receptor of CD93 on early-activated T cells. Pharmacologic inhibition of BTK or blockade of the CD93–CD69 interaction restored T-cell effector function and synergistically enhanced TCE efficacy in B-NHL and solid tumors. Collectively, these findings define a myeloid–T cell inhibitory circuit that limits TCE therapeutic responses and demonstrate that targeting the BTK-CD93-CD69 axis may synergize with TCE therapies to augment their efficacy in cancer.