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

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 ferriti...

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Main Authors: 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, Magdalena Krol
Format: Article
Language:English
Published: Nature Portfolio 2025-02-01
Series:Nature Communications
Online Access:https://doi.org/10.1038/s41467-025-56637-9
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Summary: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.
ISSN:2041-1723

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