Expert opinion on biological therapy · 2026
Breaking immune exclusion in cold tumors via TGF-β pathway inhibition.
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Zhang Minjun, Sun Yuchen, Chen Luyan, Xue Dixuan, Zhang Di, Yi Ming, Dai Zhijun
Аннотация
INTRODUCTION: Immune exclusion in cold tumors is a major mechanism of immunotherapy resistance, and TGF-β signaling acts as a key orchestrator of this process. The clinical development of TGF-β/PD-(L)1 dual-targeting agents has seen both setbacks and breakthroughs, and a critical examination of this strategy is therefore timely and translationally relevant.
AREAS COVERED: This work summarizes the mechanisms by which TGF-β drives immune exclusion through stromal remodeling, metabolic suppression, and immune cell regulation. It systematically analyzes preclinical and clinical evidence on bifunctional fusion proteins, represented by M7824 and SHR-1701, as well as bispecific antibodies. Key translational challenges, including therapeutic window constraints, biomarker development, and indication selection, are discussed. The literature search covered PubMed and major oncology conference proceedings on TGF-β/PD-(L)1 dual blockade.
EXPERT OPINION: The success of TGF-β-targeted therapy depends on moving beyond broad pathway inhibition toward biomarker-guided patient selection and context-dependent intervention. Spatially or biologically restricted targeting, multi-parametric biomarker frameworks, and mechanism-driven combination regimens are likely to define the next phase of clinical development in this field.
AREAS COVERED: This work summarizes the mechanisms by which TGF-β drives immune exclusion through stromal remodeling, metabolic suppression, and immune cell regulation. It systematically analyzes preclinical and clinical evidence on bifunctional fusion proteins, represented by M7824 and SHR-1701, as well as bispecific antibodies. Key translational challenges, including therapeutic window constraints, biomarker development, and indication selection, are discussed. The literature search covered PubMed and major oncology conference proceedings on TGF-β/PD-(L)1 dual blockade.
EXPERT OPINION: The success of TGF-β-targeted therapy depends on moving beyond broad pathway inhibition toward biomarker-guided patient selection and context-dependent intervention. Spatially or biologically restricted targeting, multi-parametric biomarker frameworks, and mechanism-driven combination regimens are likely to define the next phase of clinical development in this field.