Chemoradiation-resistant cancer cells and unresectable micro-tumors limit treatment efficacy and lead to high nonspecific toxicity or recurrence in head and neck cancers. We show the cancer cell-specific, on-demand enhancement of the chemo- and chemoradiation therapy with mechanical intracellular impact of plasmonic nanobubbles, a laser pulseinduced explosive nano-event, not a particle. We report cellular mechanisms of cancer cell-specific detection and enhancement of the entry drug and X-ray dose and validate these mechanisms in vitro and in vivo for head and neck squamous cell carcinoma. Plasmonic nanobubble technology showed more than 10-fold enhancement of the therapeutic efficacy compared to standard chemoradiation in murine models of primary, microscopic residual and recurrent diseases. At the same time our technology efficiently spared adjacent normal tissues due to the reduction of the effective therapeutic doses of drug by 30-40 fold, X-rays by 15-fold and the treatment time to a single procedure. The developed plasmonic nanobubble technology transforms a standard macro-therapy into a cell-level on-demand theranostic treatment for primary, adjuvant and adjunct applications.