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

Bartlomiej Taciak, Maciej Bialasek, Malgorzata Kubiak, Ilona Marszalek, Malgorzata Gorczak, Olha Osadchuk, Daria Kurpiel, Damian Strzemecki, Karolina Barwik, Marcin Skorzynski, Julia Nowakowska, Waldemar Lipiński, Łukasz Kiraga, Jan Brancewicz, Robert Klopfleisch, Łukasz Krzemiński, Emilia Gorka, Anna Smolarska, Irena Padzinska-Pruszynska, Małgorzata Siemińska, Jakub Guzek, Jan Kutner, Marlena Kisiala, Krzysztof Wozniak, Giacomo Parisi, Roberta Piacentini, Luca Cassetta, Lesley M. Forrester, Lubomir Bodnar, Tobias Weiss, Alberto Boffi, Paulina Kucharzewska (), Tomasz P. Rygiel () and Magdalena Krol ()
Additional contact information
Bartlomiej Taciak: Cellis AG
Maciej Bialasek: Cellis AG
Malgorzata Kubiak: Cellis AG
Ilona Marszalek: Cellis AG
Malgorzata Gorczak: Cellis AG
Olha Osadchuk: Cellis AG
Daria Kurpiel: Cellis AG
Damian Strzemecki: Cellis AG
Karolina Barwik: Cellis AG
Marcin Skorzynski: Polish Academy of Sciences
Julia Nowakowska: Cellis AG
Waldemar Lipiński: Cellis AG
Łukasz Kiraga: Cellis AG
Jan Brancewicz: Cellis AG
Robert Klopfleisch: Free University of Berlin
Łukasz Krzemiński: Biosens Labs Sp. z o.o
Emilia Gorka: Cellis AG
Anna Smolarska: Warsaw University of Life Sciences
Irena Padzinska-Pruszynska: Warsaw University of Life Sciences
Małgorzata Siemińska: Cellis AG
Jakub Guzek: Warsaw University of Life Sciences
Jan Kutner: Polish Academy of Sciences
Marlena Kisiala: University of Warsaw
Krzysztof Wozniak: University of Warsaw
Giacomo Parisi: Sapienza University of Rome
Roberta Piacentini: Sapienza University of Rome
Luca Cassetta: University of Edinburgh
Lesley M. Forrester: University of Edinburgh
Lubomir Bodnar: Cellis AG
Tobias Weiss: University Hospital and University of Zurich
Alberto Boffi: Cellis AG
Paulina Kucharzewska: Cellis AG
Tomasz P. Rygiel: Cellis AG
Magdalena Krol: Cellis AG

Nature Communications, 2025, vol. 16, issue 1, 1-30

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-56637-9

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