Cancer innervation: from mechanisms to clinical implications

The recognition of tumor innervation has evolved from a histological curiosity into a foundational principle of cancer neuroscience. The bidirectional crosstalk between nerves and cancer cells is profoundly paradoxical, exerting complex, context-dependent, and often opposing effects on tumor dynamics, thereby influencing cancer progression and patient prognosis. Through synthesizing the established knowledge of tumor innervation with the broader hallmarks of cancer, this paper seeks to delineate the reciprocal interplay and key messengers between cancer cells and nerves, assess its prognostic value, and evaluate current and emerging therapeutic strategies. Our synthesis establishes tumor innervation as an integrative component of cancer pathogenesis, where cancer cells promote neurogenesis and axonogenesis as well as recruit peripherial nerves, while nerves reciprocally disrupt key cellular homeostatic processes, contributing to canonical cancer hallmarks. While increased nerve characteristics and stress hormones are robust prognostic markers for aggressive disease and poor survival, exosomes provide complementary diagnostic value. Stress-mediated signaling through adrenergic and glucocorticoid receptors presents a druggable axis, yet monotherapies face limitations of efficacy and resistance. CAP has evolved as a promising solution, either as a standalone treatment or an adjuvant, by impairing neurogenesis and axonogenesis, remodeling tumor microenvironment for nerve recruitment blockage, and targeting cancer hallmarks. Collectively, cancer innervation has emerged as an innovative cancer hallmark, and the concept of reciprocal reprogramming, whereby cancer cells reprogram neural cells to fuel progression while nerves reciprocally reprogram the hallmarks of cancer, provides a unifying framework for understanding this bidirectional crosstalk. Leveraging this framework may advance precision medicine through targeted disruption of the tumor-nerve axis.