Phytochemicals as Emerging Antiproliferative Agents in Head and Neck Cancer: Molecular Mechanisms and Therapeutic Strategies

Background: Cancer remains a leading cause of mortality worldwide, necessitating innovative therapeutic strategies beyond conventional treatments. The increasing interest in natural and synthetic antiproliferative compounds is driven by their ability to target oncogenic pathways implicated in tumor progression, metastasis, and drug resistance. This review explores the potential of bioactive phytochemicals and molecularly targeted therapies, particularly epidermal growth factor receptor (EGFR) inhibitors, in modulating cancer cell survival, proliferation, and immune evasion. A central focus is placed on the phosphoinositide 3-kinases (PI3Ks)/protein kinase B (AKT), JAK/STAT, and mitogen-activated protein kinase (MEK)/extracellular signal-regulated kinase (ERK) signaling pathways, which are frequently dysregulated in therapy-resistant cancers, particularly head and neck cancer. Summary: Emerging evidence suggests that phytochemicals such as curcumin, resveratrol, and flavonoids not only suppress oncogenic signaling but also enhance apoptosis, inhibit epithelial-mesenchymal transition, and regulate oxidative stress responses. Additionally, recent preclinical and clinical studies indicate that combinatorial applications of phytochemicals with targeted agents can sensitize resistant tumors to chemotherapy and immunotherapy, thereby improving therapeutic efficacy. However, a major challenge limiting the clinical translation of phytochemicals is their low bioavailability and rapid metabolism. Advances in nanoparticle-based drug delivery, synthetic derivatives, and CRISPR-mediated genome editing offer promising solutions to overcome these limitations, ensuring optimal stability, targeted delivery, and enhanced anticancer activity. Key Messages: By integrating traditional phytotherapy with modern molecular oncology, this review highlights novel synergistic strategies that may revolutionize cancer treatment, paving the way for personalized anticancer therapeutics. DBCs and herbal medicine influence key oncogenic pathways, including EGFR, PI3K/AKT, and MEK/ERK. Human papillomavirus (HPV)-positive and HPV-negative tumors exhibit distinct molecular profiles, affecting their response to conventional treatments and adjunctive therapies. Polyphenols such as curcumin, resveratrol, and quercetin, along with herbal extracts including Scutellaria baicalensis and Camellia sinensis, demonstrate the ability to modulate oxidative stress, apoptosis, and immune responses while reducing therapy resistance. Nanoparticle-based formulations improve the bioavailability of these compounds, enhancing their anticancer effects. However, their effectiveness varies based on the HPV status of the tumor, with HPV-positive cancers showing greater sensitivity to immune-modulating compounds. .