ABSTRACT: Recalcitrant tumors pose a significant clinical challenge because of their biological complexity and resistance to conventional therapies. These tumors develop mechanisms to evade drug toxicity, including alterations in drug metabolism, enhanced DNA repair capabilities, and changes in the tumor microenvironment that support their survival. The lack of identifiable molecular targets in many recalcitrant cancers limits precision medicine approaches, necessitating the development of novel therapeutic strategies. Early diagnosis remains difficult because these tumors present with nonspecific symptoms or are detected at advanced stages when treatments are less effective, contributing to poor outcomes. Emerging epidemiological studies have highlighted the role of lifestyle modifications in tumor onset and progression. Advances in molecular biology and genomics have enabled the identification of new biomarkers and therapeutic targets, leading to innovative approaches including immunotherapy, targeted therapy, and combination therapies to overcome resistance. This narrative review emphasizes integrated prevention strategies, including lifestyle interventions, summarizes progress in understanding recalcitrant tumor pathophysiology, and evaluates current and experimental treatments to improve survival rates and quality of life for patients.

Impact statement: This review investigates the primary factors that render recalcitrant tumors incurable and evaluates prospective strategies for enhancing early diagnosis, prevention, and the overcoming of therapeutic resistance.

Key words: Recalcitrant tumor; nutrition; immuno-checkpoint inhibitor; replication stress response; tumor stiffness.