Fig. 4: A VSN-mediated interoceptive pathway drives sympathetic efferent activities in the lung TME.

a,b, Representative images and quantification of Slc17a6 (red) and Fos (cyan) by RNAscope in RVLM neurons from healthy (n = 5), KP tumour-bearing Trpv1-cre; LSL-DTR (a) or Npy2r-IRES-cre; LSL-DTR (b) mice that were injected with PBS or DT in the VNG (a: n = 7 PBS, n = 5 DT, P < 0.0001 for PBS versus healthy and PBS versus DT; b: n = 5 PBS, n = 6 DT, P < 0.0001). Scale bars, 100 μm. c, Representative immunofluorescence images and quantification of FOS⁺ neurons in T3–5 thoracic ganglia from healthy (n = 4) or tumour-bearing Npy2r-IRES-cre; LSL-DTR mice injected with PBS (n = 4) or DT (n = 4) in the VNG. P < 0.0001 for PBS versus healthy and PBS versus DT. Scale bars, 50 μm. d, Experimental setup (top), representative H&E-stained lung sections (bottom left) and quantification of lung tumour burden (bottom right) from Vglut2-cre mice injected with AAV-DIO-mCherry (control, n = 6) or AAV-DIO-hM4Di (hM4Di, n = 5) in the RVLM. P = 0.0062. Scale bars, 1 mm. e, Representative immunofluorescence images and quantification of TH⁺ sympathetic nerves (green) around KP tumours (red) from Trpv1-cre; LSL-DTR mice that received VNG injection of PBS or DT. The number of TH⁺ nerves around each tumour (n = 153 PBS, n = 75 DT, P < 0.0001) as well as the average number of TH⁺ nerve fibres per tumour in each mouse (n = 13 PBS, n = 10 DT, P = 0.0011) were quantified. 5.1× and 1.3× refer to the fold change between indicated groups. Scale bars, 100 μm. f, Noradrenaline levels in tumour-bearing lung tissue from Npy2r-IRES-cre; LSL-DTR mice that received VNG injection of PBS (n = 5) or DT (n = 6). P = 0.0165 by tissue mass, P = 0.0044 by lung lobe. g, Quantification of VAChT⁺ parasympathetic nerves around tdTomato⁺ tumours from Trpv1-cre; LSL-DTR mice that received VNG injection of PBS or DT. The number of VAChT⁺ nerves around each tumour (n = 95 PBS, n = 40 DT) as well as the average number of VAChT⁺ nerve fibres per tumour in each mouse (n = 7 PBS, n = 5 DT) were quantified. Results shown are representative of two independent experiments. Data are expressed as mean ± s.e.m. One-way ANOVA with Tukey’s multiple comparisons (a,c) or unpaired, two-tailed Student’s t-test (b,d–g) was performed. Brain cartoons in a,b,d were created in BioRender. Jin, C. (2026) https://BioRender.com/9zdoahw.

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