Surface enhanced Raman scattering (SERS) based on chemical mechanism (CM) has attracted tremendous attention for its great selectivity and stability. However, extremely low enhancement factor (EF) limits its practical applications for trace detection. Here, a novel sponge-like Cu-doping SnO2-NiO p-n semiconductor heterostructure (SnO2-NiOx/Cu), was first designed and created as a CM-based SERS substrate with a significant EF of 1.66 × 1010. This remarkable EF was mainly attributed to the enhanced charge-separation efficacy of p-n heterojunction and charge transfer resonance resulted from Cu doping. Moreover, the porous sponge structure enriched the probe molecules, resulting in further SERS signals magnification. By immobilizing copper phthalocyanine as an inner-reference element, SnO2-NiOx/Cu was developed as a SERS nose for selective recognition of multiple lung cancer related-volatile organic compounds (VOCs) down to ppb level. The information of VOCs was recorded in a barcode, demonstrating practical potential of a desktop SERS device for biomarker screening.