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

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.

Authors

Institutions

Publication Details

Journal
Nature Communications
Published
2025-02-04
DOI
https://doi.org/10.1038/s41467-025-56637-9
Citations
12
Primary Topic
Phagocytosis and Immune Regulation
Type
article
Field-Weighted Citation Impact
9.57

Funders

Controls
|||
ALL TIME
JAN
FEB
MAR
APR
MAY
JUN
JUL
AUG
SEP
OCT
article

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

Waldemar Lipiński, Robert Klopfleisch, Maciej Białasek, Marcin Skorzynski et al.
12 citations
Nature Communications
Phagocytosis and Immune Regulation
9.57
article

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

Waldemar Lipiński, Robert Klopfleisch, Maciej Białasek, Marcin Skorzynski, Małgorzata Górczak, Tobias Weiß, Anna Smolarska, Luca Cassetta, Łukasz Kiraga, Irena Padzińska-Pruszyńska, Jan Kutner, J Nowakowska, Lubomir Bodnar, Małgorzata Kubiak, Giacomo Parisi, Emilia Górka, Tomasz P. Rygiel, Damian Strzemecki, M. Kisiala, Ilona Marszałek, Krzysztof Woźniak, Paulina Kucharzewska, Małgorzata Siemińska, Roberta Piacentini, Magdalena Król, Lesley M. Forrester, Bartłomiej Taciak, Olha Osadchuk, Daria Kurpiel, Łukasz Krzemiński, Alberto Boffi, Jan Brancewicz, Jakub Guzek, Karolina Barwik
article en
12 citations

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.

Nature CommunicationsVol. 16(1)
Warsaw University of Life Sciences (PL), University of Zurich (CH), University of Siedlce (PL), Italian Institute of Technology (IT), Takeda (Switzerland) (CH), University Hospital of Zurich (CH), MRC Centre for Regenerative Medicine (GB), MRC Centre for Reproductive Health (GB), Cells Therapy (Poland) (PL), Mossakowski Medical Research Institute, Polish Academy of Sciences (PL), Cell Medica (Switzerland) (CH), University of Warsaw (PL), Freie Universität Berlin (DE), Sapienza University of Rome (IT), University of Edinburgh (GB), Polish Academy of Sciences (PL)
Warszawski Uniwersytet Medyczny, Uniwersytet Warszawski, Szkola Glówna Gospodarstwa Wiejskiego w Warszawie, Medical Research Council, Institute of Molecular and Cell Biology
Good health and well-being
Openalex Percentile: Top 2%
Phagocytosis and Immune Regulation
9.57
DOIOpen Access PDFOpenAlex
AI Navigator

Ask Laika to Summarize, Analyze, and Connect papers live on the map.

Summarize Papers & Methodologies

Extract key findings, datasets, and comparative methods across publications.

Benchmark Rankings & Visual Analytics

Rank top research institutions, authors, funders, topics, and journals by Field-Weighted Citation Impact (FWCI) and paper volume with instant charts.

Connect Distant Disciplines

Bridge topological clusters on the map to find hidden collaborative intersections.