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.
Authors
- Adam Doherty (ORCID: https://orcid.org/0000-0002-1673-0337)
- Patrizia Cristofori
- Alex Pezzotta (ORCID: https://orcid.org/0000-0003-1788-5880)
- Elisa Setten (ORCID: https://orcid.org/0000-0001-6363-3823)
- Guido Francesco Fumagalli (ORCID: https://orcid.org/0000-0003-2195-4973)
- Giorgio Malpeli (ORCID: https://orcid.org/0000-0002-2996-2903)
- Francesca Cersosimo (ORCID: https://orcid.org/0000-0002-8338-9968)
- M. Locati
- Patrizia Bossolasco (ORCID: https://orcid.org/0000-0002-1596-7818)
- Loris Mannino (ORCID: https://orcid.org/0000-0001-9542-9384)
- Chiara Cavallini (ORCID: https://orcid.org/0000-0002-2470-0162)
- Emanuela Bottani (ORCID: https://orcid.org/0000-0003-1217-8722)
- Eugenio Scanziani (ORCID: https://orcid.org/0000-0003-3996-5048)
- Sissi Dolci (ORCID: https://orcid.org/0000-0001-8230-8065)
- Kristin Schubert (ORCID: https://orcid.org/0000-0003-4365-084X)
- Z. Malik (ORCID: https://orcid.org/0000-0003-0882-5480)
- Eros Rossi
- Maria Teresa Scupoli (ORCID: https://orcid.org/0000-0002-3352-7859)
- Anna Pistocchi (ORCID: https://orcid.org/0000-0001-9467-2542)
- G. Pruonto (ORCID: https://orcid.org/0000-0002-4644-9714)
- Alessandra Castagna (ORCID: https://orcid.org/0000-0001-5177-3693)
- Marco Endrizzi (ORCID: https://orcid.org/0000-0002-7810-2301)
- Giuseppe Busetto (ORCID: https://orcid.org/0000-0003-4281-8081)
- Alessandra Campanelli (ORCID: https://orcid.org/0000-0003-4818-3996)
- Benedetta Savino (ORCID: https://orcid.org/0000-0002-2996-9515)
- Isabel Karkossa (ORCID: https://orcid.org/0000-0003-2781-1877)
- Benedetta Lucidi
- Alessia Amenta (ORCID: https://orcid.org/0000-0002-4868-3678)
- Nicolò Martinelli (ORCID: https://orcid.org/0000-0001-6857-0729)
- Marzia Di Chio (ORCID: https://orcid.org/0000-0003-1434-6101)
- I. Decimo
- Federico Boschi (ORCID: https://orcid.org/0000-0001-9623-6859)
- Stefano Gianoli (ORCID: https://orcid.org/0000-0001-6857-3305)
- Nicola Piazza (ORCID: https://orcid.org/0009-0004-9343-9457)
- Ludovica Sagripanti
- Francesco Bifari
- Marco Sandri
- Silvia Ferretti
- Francesca Ciarpella
- Ilaria Barone
- Vincenzo Silani
Institutions
- University of Verona (IT)
- Helmholtz Centre for Environmental Research (DE)
- University of Milan (IT)
- The Francis Crick Institute (GB)
- IRCCS Istituto Auxologico Italiano (IT)
- Istituti di Ricovero e Cura a Carattere Scientifico (IT)
- IRCCS Humanitas Research Hospital (IT)
- University College London (GB)
- University of Milano-Bicocca (IT)
Publication Details
- Journal
- Immunity
- Published
- 2026-01-26
- DOI
- https://doi.org/10.1016/j.immuni.2025.12.016
- Citations
- 1
- Primary Topic
- Immune cells in cancer
- Type
- article
- Field-Weighted Citation Impact
- 24.43
Funders
- Wellcome Trust
- Cancer Research UK
- Ministero dell’Istruzione, dell’Università e della Ricerca
- Università degli Studi di Verona
- Medical Research Council
- Engineering and Physical Sciences Research Council