LAUSR

Cancer arises from malignant cells that exist in dynamic multilevel interactions with the host tissue. Cancer therapies aiming to directly kill cancer cells, including oncogene-targeted therapy and immune-checkpoint therapy that revives tumour-reactive cytotoxic T lymphocytes, are effective in some patients 1 , 2 , but acquired resistance frequently develops 3 , 4 . An alternative therapeutic strategy aims to rectify the host tissue pathology, including abnormalities in the vasculature that foster cancer progression 5 , 6 ; however, neutralization of proangiogenic factors such as vascular endothelial growth factor A (VEGFA) has had limited clinical benefits 7 , 8 . Here, following the finding that transforming growth factor-β (TGF-β) suppresses T helper 2 (T H 2)-cell-mediated cancer immunity 9 , we show that blocking TGF-β signalling in CD4 + T cells remodels the tumour microenvironment and restrains cancer progression. In a mouse model of breast cancer resistant to immune-checkpoint or anti-VEGF therapies 10 , 11 , inducible genetic deletion of the TGF-β receptor II (TGFBR2) in CD4 + T cells suppressed tumour growth. For pharmacological blockade, we engineered a bispecific receptor decoy by attaching the TGF-β-neutralizing TGFBR2 extracellular domain to ibalizumab, a non-immunosuppressive CD4 antibody 12 , 13 , and named it CD4 TGF-β Trap (4T-Trap). Compared with a non-targeted TGF-β-Trap, 4T-Trap selectively inhibited T H cell TGF-β signalling in tumour-draining lymph nodes, causing reorganization of tumour vasculature and cancer cell death, a process dependent on the T H 2 cytokine interleukin-4 (IL-4). Notably, the 4T-Trap-induced tumour tissue hypoxia led to increased VEGFA expression. VEGF inhibition enhanced the starvation-triggered cancer cell death and amplified the antitumour effect of 4T-Trap. Thus, targeted TGF-β signalling blockade in helper T cells elicits an effective tissue-level cancer defence response that can provide a basis for therapies directed towards the cancer environment. 4T-Trap, a bispecific molecule designed to recognize CD4 and bind TGF-β, blocks TGF-β signalling in T helper cells, causing interleukin-4-dependent vascular reorganization and cancer cell death in a mouse model of breast cancer.