Tumor-associated macrophages enhance peripheral nerve tumor infiltration and spinal cord repair.

Tumor-associated macrophages (TAMs) enhance cancer progression by promoting angiogenesis, extracellular matrix remodeling, and immune suppression. Nerve infiltration also contributes to tumor growth. However, the role of TAMs in promoting intratumoral nerve growth remains unclear. In this study, we have shown that TAMs express a distinct neural growth gene signature. TAMs actively enhanced neural growth within tumors and directly promoted in vitro neurite outgrowth. We identified secreted phosphoprotein 1 (SPP1) as a required mediator of TAM-driven neural growth and mTORC2 activation. Leveraging this TAM-neural growth function, we explored TAM neuroregenerative potential. Adoptive transfer of TAMs in severe complete-compressive-contusive spinal cord injury (scSCI) increased neuronal survival, axonal regrowth, and motor function recovery. Moreover, TAMs healed scSCI microenvironment and remodeled the cyst. Functional and proteomic analyses confirmed SPP1 and neural Rictor as necessary molecular mediators for TAM-induced regeneration. Our data unveil a role for TAMs in tumor innervation and neural tissue repair.