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  3. Harnessing macrophage-drug conjugates for allogeneic cell-based therapy of solid tumors via the TRAIN mechanism

Harnessing macrophage-drug conjugates for allogeneic cell-based therapy of solid tumors via the TRAIN mechanism

  • Nat Commun. 2025 Feb 4;16(1):1327. doi: 10.1038/s41467-025-56637-9.
Bartlomiej Taciak # 1 2,  Maciej Bialasek # 1 2,  Malgorzata Kubiak # 1 2,  Ilona Marszalek 1,  Malgorzata Gorczak 1 2,  Olha Osadchuk 1,  Daria Kurpiel 1,  Damian Strzemecki 1,  Karolina Barwik 1,  Marcin Skorzynski 3,  Julia Nowakowska 1 2,  Waldemar Lipiński 1,  Łukasz Kiraga 1 2,  Jan Brancewicz 1,  Robert Klopfleisch 4,  Łukasz Krzemiński 5,  Emilia Gorka 1 2,  Anna Smolarska 2,  Irena Padzinska-Pruszynska 2,  Małgorzata Siemińska 1,  Jakub Guzek 2,  Jan Kutner 6,  Marlena Kisiala 7,  Krzysztof Wozniak 7,  Giacomo Parisi 8 9,  Roberta Piacentini 8 9,  Luca Cassetta 10,  Lesley M Forrester 11,  Lubomir Bodnar 1 12,  Tobias Weiss 13,  Alberto Boffi 1 8 9,  Paulina Kucharzewska 14 15,  Tomasz P Rygiel 16 17,  Magdalena Krol 18 19
Affiliations

Affiliations

  • 1 Cellis AG, Zurich, Switzerland.
  • 2 Center of Cellular Immunotherapies, Warsaw University of Life Sciences, Warsaw, Poland.
  • 3 Department of Immunology, Mossakowski Medical Research Institute, Polish Academy of Sciences, Warsaw, Poland.
  • 4 Institute of Veterinary Pathology, Free University of Berlin, Berlin, Germany.
  • 5 Biosens Labs Sp. z o.o, Warsaw, Poland.
  • 6 The International Institute of Molecular Mechanisms and Machines, Polish Academy of Sciences, Warsaw, Poland.
  • 7 Department of Chemistry, Biological and Chemical Research Centre, University of Warsaw, Warsaw, Poland.
  • 8 Department of Biochemical Sciences "Alessandro Rossi Fanelli", Sapienza University of Rome, Rome, Italy.
  • 9 Center of Life Nano and Neuro Science, Institute of Italian Technology, Rome, Italy.
  • 10 MRC Centre for Reproductive Health, Queen Medical Research Institute, University of Edinburgh, Edinburgh, UK.
  • 11 Centre for Regenerative Medicine, University of Edinburgh, Edinburgh, UK.
  • 12 Faculty of Medical and Health Sciences, Siedlce University of Natural Sciences and Humanities, Siedlce, Poland.
  • 13 Department of Neurology, Clinical Neuroscience Center, University Hospital and University of Zurich, Zurich, Switzerland.
  • 14 Cellis AG, Zurich, Switzerland. paulina_kucharzewska_siembieda@sggw.edu.pl.
  • 15 Center of Cellular Immunotherapies, Warsaw University of Life Sciences, Warsaw, Poland. paulina_kucharzewska_siembieda@sggw.edu.pl.
  • 16 Cellis AG, Zurich, Switzerland. t.rygiel@cellis.eu.
  • 17 Department of Immunology, Mossakowski Medical Research Institute, Polish Academy of Sciences, Warsaw, Poland. t.rygiel@cellis.eu.
  • 18 Cellis AG, Zurich, Switzerland. m.krol@cellis.eu.
  • 19 Center of Cellular Immunotherapies, Warsaw University of Life Sciences, Warsaw, Poland. m.krol@cellis.eu.
  • # Contributed equally.
PMID: 39900573 DOI: 10.1038/s41467-025-56637-9
Abstract

Treatment of solid tumors remains challenging and therapeutic strategies require continuous development. Tumor-infiltrating macrophages play a pivotal role in tumor dynamics. Here, we present a Macrophage-Drug Conjugate (MDC) platform technology that enables loading macrophages with ferritin-drug complexes. We first show that macrophages actively take up human heavy chain ferritin (HFt) in vitro via macrophage scavenger receptor 1 (MSR1). We further manifest that drug-loaded macrophages transfer ferritin to adjacent Cancer cells through a process termed 'TRAnsfer of Iron-binding protein' (TRAIN). The TRAIN process requires direct cell-to-cell contact and an immune synapse-like structure. At last, MDCs with various anti-cancer drugs are formulated with their safety and anti-tumor efficacy validated in multiple syngeneic mice and orthotopic human tumor models via different routes of administration. Importantly, MDCs can be prepared in advance and used as thawed products, supporting their clinical applicability. This MDC approach thus represents a promising advancement in the therapeutic landscape for solid tumors.

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