Beyond neurotransmission: A hypothetical framework for non-canonical dopamine receptor signaling in lung cancer pathobiology and therapy resistance.

Lung cancer therapy is often limited by drug resistance, an ecosystem-level process that remains poorly understood. The pleiotropic and paradoxical roles of dopamine receptors in this disease defy classical neurotransmission-based explanations. Here, we advance a "node-and-network" perspective. In lung cancer, dopamine receptors may engage non-canonical modes including β-arrestin-dependent signaling, receptor heterodimerization and voltage-sensitive conformational modulation. Dopamine receptor activity has been separately associated with three resistance-related modules: the "pump" (drug efflux), the "fuel" (metabolic reprogramming), and the "sanctuary" (microenvironmental remodeling). However, these observations come from distinct experimental systems, and it remains unclear whether dopamine receptors coordinately regulate all three modules in a unified malignant ecosystem. We hypothesize that dopamine receptor-targeted therapies may perturb individual resistance modules, rather than disrupt an established integrated network. This framework redefines dopamine receptors beyond canonical neurotransmitter sensors and provides a hypothetical model built on preclinical and cross-system findings, which requires comprehensive validation in lung cancer models.