Bifunctional Phagocytic Synapse Enhancers Remodel the Tumor Microenvironment to Overcome Immunosuppression
Year: 2026
Type: article
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.
Source: Cancer Research
Authors: Valerio Sabatino, Cong Tang, Rita C. Acúrcio, Ana R. Coelho, Felix M. Müller, Márcia Fontes, Wei Ting Khaw, Carlos Labão-Almeida, Derrick R. Hicks, Wei Yang, Aldrin Vasco Vidal, Irene Sarkar, Debarati Shome, Mar Cabeza-Cabrerizo, Theresa V. Rohm, Silvan Fleisch, Alexandra Gerber, Sabrina A. Hogan, Fiona Gerster, Deniz Kaymak, Stanislav Pantelyushin, Johannes vom Berg, Lu Li, Rogier M. Reijmers, Rita Fior, David Baker, Helena F. Florindo, Gregor Hutter, Gonçalo J.L. Bernardes
Institutions: University of Cambridge, University Hospital of Basel, Gulbenkian Institute for Molecular Medicine, University of Lisbon, Champalimaud Foundation, Spanish National Cancer Research Centre, University of Washington, University of California San Diego, University of Zurich, Howard Hughes Medical Institute
Language: English
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Awards: Phagocytic Synapse Enhancers for the Immunotherapy of Cancer, G3999658136, Combined Microglia Modulation and Tumor Targeting Against Glioblastoma, Nano-Immunotherapy Decoding and Targeting Immune Checkpoint-resistant Tumors, G683472059, Reversible PROTACs for Targeted Cancer Therapy, G9001171226, G9001174636, G9001174674, G9001175811
OpenAlex ID: W7208724013