Journal Article

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

Lipiński, Waldemar, Osadchuk, Olha, Krol, Magdalena, Padzinska-Pruszynska, Irena, Barwik, Karolina, Smolarska, Anna, Piacentini, Roberta, Cassetta, Luca, Boffi, Alberto, Kisiala, Marlena, Forrester, Lesley M., Kucharzewska, Paulina, Skorzynski, Marcin, Bodnar, Lubomir, Kiraga, Łukasz, Kutner, Jan, Weiss, Tobias, Brancewicz, Jan, Marszalek, Ilona, Kubiak, Malgorzata, Nowakowska, Julia, Taciak, Bartlomiej, Strzemecki, Damian, Kurpiel, Daria, Guzek, Jakub, Rygiel, Tomasz P., Wozniak, Krzysztof, Bialasek, Maciej, Gorka, Emilia, Krzemiński, Łukasz, Parisi, Giacomo, Gorczak, Malgorzata, Siemińska, Małgorzata, Klopfleisch, Robert

2025

Overview

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. Treatment strategy of solid tumors requires continuous development. Here the authors develop a Macrophage Drug Conjugate (MDC) platform by loading ferritin-drug complexes to macrophages. MDC transfers the ferritin to cancer cells via ‘TRAnsfer of Iron binding protein’ (TRAIN) process and reduces tumor volume in various mouse tumor models.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 13/1 / 13/109 / 13/21 / 13/31 / 13/44 / 13/95 / 14 / 14/19 / 14/34 / 14/35 / 14/63 / 14/69 / 38 / 38/44 / 59/5 / 631/250/2504/342 / 631/67/1059/153 / 631/67/1059/2325 / 631/80/2023/2022 / 64/60 / 82/16 / 82/29 / 82/51 / 82/58 / 82/83 / Animal models / Animals / Anticancer properties / Antineoplastic Agents - administration & dosage / Antineoplastic Agents - pharmacology / Antineoplastic drugs / Apoferritins - metabolism / Cancer / Cell Line, Tumor / Cell- and Tissue-Based Therapy - methods / Conjugates / Drug development / Female / Ferritin / Humanities and Social Sciences / Humans / Immunosuppressive agents / Iron / Iron-binding protein / Macrophages / Macrophages - metabolism / Mice / Mice, Inbred C57BL / multidisciplinary / Neoplasms - therapy / Proteins / Scavenger receptors / Science / Science (multidisciplinary) / Solid tumors / Tumors / Xenograft Model Antitumor Assays