Chimeric antigen receptor (CAR)-T cell therapy has achieved complete remission rates approaching 80% in hematologic malignancies. however, its efficacy in solid tumors remains limited. CAR-T cells exhibit poor tumor infiltration, undergo functional exhaustion within the immunosuppressive tumor microenvironment (TME), and may induce severe on-target off-tumor toxicity due to their single-antigen recognition architecture when target antigens are expressed on normal tissues.

In this study, we sought to overcome these limitations using engineered macrophages capable of actively sensing the tumor microenvironment and conditionally secreting multifunctional payloads. This platform integrates four key mechanisms: (1) active payload delivery mediated by the intrinsic tumor tropism of macrophages; (2) direct antitumor activity through pan-receptor tyrosine kinase (RTK) inhibition by decorin; (3) prevention of payload leakage via collagen binding of decorin, thereby enabling tumor-localized retention; and (4) activation of subsequent CAR-T cells exclusively within the tumor site through a fused CD19 epitope functioning as a synthetic neoantigen. Collectively, engineered macrophages sense tumor-associated signals to conditionally regulate payload expression, while a single secreted payload simultaneously mediates antitumor activity, tumor-site localization, and CAR-T cell activation.

Taken together, this study presents a novel cooperative immune cell therapy strategy that repurposes the innate properties of macrophages into a tumor-sensing circuit and employs multifunctional payloads to simultaneously mediate antitumor effects and downstream immune cell activation. This approach provides a potential framework for improving both the safety and therapeutic efficacy of solid tumor immunotherapy.