Electrical activity powered neural circuit sustains systemic immune evasion in gastric cancer

Background: Nociceptive sensory nerves are emerging as active regulators of tumor progression and immune suppression within the tumor microenvironment (TME). We previously showed that gastric cancer cells establish a bi-directional electrical circuit with CGRP⁺ sensory neurons, in which cancer depolarization triggers neuronal firing and CGRP release. Given that sensory afferents serve as the afferent limb of the inflammatory reflex transmitting peripheral signals to the brainstem, we hypothesized that cancer may similarly exploit neural circuits and neuropeptide signaling to regulate systemic immunity. Methods: A chemogenetic receptor (PSAM4-5HT₃) was introduced into a syngeneic murine (ACKP) gastric cancer cell line to evoke cancer depolarization in vivo. Cancer-activated neuronal projections were mapped in TRAP2 (Fos-CreERT2) mice using Cre-dependent AAV reporters. Immune profiling was performed to characterize antigen-experienced T cells in the tumor-draining lymph node (TDLN) and various CD8⁺ T-cell subsets within the TME. In vivo imaging was used to monitor T-cell motility dynamics, and GCaMP6s was expressed in immune cells to visualize neuron-triggered calcium flux. Results: Cancer depolarization activated nociceptive sensory neurons, which established synapse-like contacts with CD8⁺ TILs preferentially at the perivascular niche and tertiary lymphoid structures. The cancer-coupled sensory nerves upregulated Cxcl10, attracting T cells toward their terminals to form these connections. In a 3-D co-culture system comprising cancer spheroids, dorsal root ganglia, and CD8⁺ TILs, optogenetic stimulation of cancer cells induced a calcium flux in sensory nerve-connected T cells, confirming functional transmission. Local activation of this cancer-nerve-T-cell circuit enhanced T-cell migration toward nerve terminals but diminished effector capacity, evidenced by reduced TNFalpha and IFNgamma expression and limited infiltration into the tumor core. Sensory afferents relayed signals to higher brainstem areas, including the nucleus tractus solitarius (NTS) and rostral ventrolateral medulla (RVLM), eliciting sympathetic output to the TDLN. This afferent-brain-efferent loop retained and immobilized antigen-experienced CD44⁺PD-1⁺ T cells within the TDLN, thereby restraining systemic immunity in a norepinephrine-Adrb2-dependent manner. Anti-PD-1 therapy paradoxically strengthens the cancer-sensory nerve coupling. Ablatio of this cancer-evoked neural circuit restored T-cell effector function systemically and synergized with anti-PD-1 therapy. Conclusions: These findings reveal that cancer depolarization activates CGRP⁺ sensory neurons to form synaptic contacts with CD8⁺ T cells, linking local peptidergic signaling to systemic immune suppression via the NTS-RVLM-TDLN axis. Disrupting this circuit restores T-cell function and enhances anti-PD-1 response.