Nerve infiltration of bladder cancer predicts response to immunotherapy

Immune checkpoint therapy (ICT), particularly Programmed Death-1 (PD1) antibody treatment, has revolutionized the clinical management of many previously undruggable types bladder cancer (BC). However, it remains unclear whether nerve-invaded BC patients benefit from immunotherapy. Here, we utilized public databases to show that BC patients with high neural signal expression are associated with more advanced tumor stages. Analysis of patient tumor samples revealed significant neural expression within classical tertiary lymphoid structures, and this was inversely correlated with the immune levels. In a denervated mouse bladder tumor model, we found that nerve ablation significantly inhibited tumor progression. Single-nucleus RNA sequencing data revealed that nerve fibers suppressed the activity of immune cells within the tumor microenvironment, while denervation alleviated immune suppression and restored cytotoxic activity. Denervation enhanced the immune response by downregulating Pdcd1 (encoded Pd1) expression in natural killer (NK) cells. Pathological analysis of patient tumor samples further confirmed that higher neural abundance was strongly correlated with PD1 expression. Finally, through database analysis and clinical sample validation, we demonstrated that BC patients with high neural signaling showed better responses to ICT. Overall, this study highlights the potential for targeted immunotherapy in nerve-invasive BC, providing a novel framework for enhancing the effectiveness of ICT in treating this subset of bladder cancer.