Bifunctional Phagocytic Synapse Enhancers Remodel the Tumor Microenvironment to Overcome Immunosuppression

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Publication Details

Journal
Cancer Research
Published
2026-09-04
DOI
https://doi.org/10.1158/0008-5472.can-25-5578
Primary Topic
Monoclonal and Polyclonal Antibodies Research
Type
article
Field-Weighted Citation Impact
0.00
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article

Bifunctional Phagocytic Synapse Enhancers Remodel the Tumor Microenvironment to Overcome Immunosuppression

Valerio Sabatino, Rogier M. Reijmers, Theresa V. Rohm, Carlos Labão‐Almeida et al.
Cancer Research
Monoclonal and Polyclonal Antibodies Research
article

Bifunctional Phagocytic Synapse Enhancers Remodel the Tumor Microenvironment to Overcome Immunosuppression

Valerio Sabatino, Rogier M. Reijmers, Theresa V. Rohm, Carlos Labão‐Almeida, Aldrin V. Vasco, Gregor Hütter, Márcia Fontes, Debarati Shome, Rita C. Acúrcio, Deniz Kaymak, Stanislav Pantelyushin, Felix Müller, Derrick R. Hicks, Gonçalo J. L. Bernardes, David Baker, Ana R. Coelho, Cong Tang, Rita Fior, Helena F. Florindo, Sabrina A. Hogan, Irene Sarkar, Johannes vom Berg, Mar Cabeza-Cabrerizo, Wei Yang, Fiona Gerster, Silvan Fleisch, Wei Ting Khaw, Alexandra Gerber, Lu Li
article en

Abstract

Current immunotherapies often fail in immunologically "cold", macrophage-rich tumor microenvironments (TMEs). Multi-targeting approaches that modulate innate-adaptive immune activation represent a promising frontier in cancer immunotherapy. Here, we developed phagocytic synapse enhancers (PSEs), a class of modular immune engagers comprising a high-affinity PD-L1 binder coupled to a macrophage-stimulating peptide, tuftsin. PSEs strengthened effector-target cell interactions and enhanced tumor phagocytosis by bridging tumor PD-L1 to macrophage neuropilin-1 (NRP1), bypassing the classical FcγR-dependent pathways. The PSEs also acted in cis on PD-L1+ macrophages, accelerating the endocytosis and lysosomal compartmentalization of surface PD-L1, therefore stripping the immunosuppressive checkpoint from the local microenvironment. Beyond physical clearance, PSEs reprogrammed macrophage phenotype and triggered a robust pro-inflammatory cytokine and chemokine response. The lead molecule, longPSE, and its half-life-extended variant fused to the albumin binding domain, ABD- longPSE, showcased superior efficacy than the macrophage enhancer magrolimab in a syngeneic tumor model of colorectal cancer and an orthotopic model of pancreatic cancer. PSE treatment remodeled the TME by inducing phenotypic changes in the lymphoid and myeloid compartments, together with a reduction of tumor-associated macrophages and regulatory T cells. These findings establish PSEs as bifunctional molecules that complement innate and adaptive immune modulation. The bifunctional design offers a versatile approach for next-generation immunotherapies and provides a blueprint for a plug-and-play platform of immune engagers targeting diverse cancer-associated pathways.

Cancer Research
Luminex (United States) (US), Champalimaud Foundation (PT), University of Lisbon (PT), University of San Diego (US), University of Washington (US), University of Zurich (CH), University Hospital of Basel (CH), University of California San Diego (US), Cambridge School (PT), Bridge University (SS), University of Washington Applied Physics Laboratory (US), Shanghai Center For Bioinformation Technology (CN), Instituto Gulbenkian de Ciência (PT)
Openalex Percentile: Top 11%
Monoclonal and Polyclonal Antibodies Research
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