Targeting ANXA1/TRKA axis enhances immunotherapy sensitivity in neural invasion-positive gastric cancer.

Gastric cancer (GC) remains a leading cause of cancer-related morbidity and mortality worldwide. Neural invasion (NI) is a common pathological behavior that worsens the prognosis in GC. However, the immune microenvironment of neural invasion-positive GC (NI(+)GC) and its potential therapeutic implications remain poorly defined. Here, we performed single-cell RNA sequencing (scRNA-seq) on tumor specimens from patients with NI(+)GC and neural invasion-negative GC (NI(-)GC) to comprehensively delineate the immune landscape. Our analysis revealed a significant enrichment of exhausted ANXA1(+)CD8(+)T cells within NI(+)GC tissues, which was validated by flow cytometry and multiplex immunohistochemistry assays. Clinically, patients with greater infiltration of ANXA1(+)CD8(+) T cells had worse overall survival and disease progression. Mechanistically, ANXA1 bound to TRKA via N-terminal region, blocking NEDD4L-mediated ubiquitination and degradation of TRKA, thereby suppressing glycolytic metabolism and driving CD8⁺T cell exhaustion. Tumor-derived nerve growth factor (NGF) further amplified this exhaustion via TRKA engagement. Importantly, treatment with an ANXA1-derived peptide (A11) combined with TRKA inhibitors synergistically reversed T cell exhaustion and suppressed tumor growth in preclinical models. These findings unveil distinctive features of the immune microenvironment in NI(+)GC and elucidate the underlying molecular mechanisms of ANXA1/TRKA axis in facilitating immune evasion, which offer new insights for enhancing the sensitivity of immunotherapy to NI(+)GC patients.