Spatial mapping of the immunotherapy-refractory tumors provides insights into cancer-induced nerve injury as a novel mechanism of immunotherapy resistance

Perineural invasion (PNI) is a well-established factor of poor prognosis in multiple cancer types, yet its mechanism remains unclear. By using a multi-omics approach, overlay of multiple spatial analysis techniques on patient-derived samples, followed by in vitro and in vivo validation, we obtained mechanistic insights into the roles of PNI and cancer-induced nerve injury (CINI) in resistance to anti-PD-1 therapy. Our study demonstrates that PNI and CINI of tumor-associated nerves are associated with poor response to anti-PD-1 therapy among patients with cutaneous squamous cell carcinoma, melanoma and gastric cancer. Electron microscopy and electrical conduction analyses reveal that cancer cells degrade the nerve fibre myelin sheets. The injured neurons respond by autonomously initiating IL-6- and type I interferon-mediated inflammation to promote nerve healing and regeneration. As the tumour grows, the CINI burden increases, and its associated inflammation becomes chronic and skews the general immune tone within the tumor microenvironment into a suppressive and exhaustive state. The CINI-driven anti-PD-1 resistance can be reversed by targeting multiple steps in the CINI signaling process: denervating the tumor, conditional knockout of the transcription factor mediating the injury signal within neurons (Atf3), knockout of the interferon-α receptor (Ifnar1−/−), or by combining anti-PD-1 and anti-IL-6 receptor blockade. Our findings demonstrate the direct immunoregulatory roles of CINI and its therapeutic potential; the ability of neurons to interpedently induce inflammation; and the critical contribution of spatial analysis to uncovering novel immunotherapy resistance mechanisms.

Learning Objectives: 

• Identify how cancer-induced nerve injury contributes to immunotherapy resistance.
• Recognize the value of multiomics and spatial analysis in uncovering tumor-nerve interactions.
• Assess therapeutic strategies targeting inflammation and neuronal signaling to enhance anti-PD-1 efficacy.