Targeted Therapies in the Most Common Advanced Solid Tumors, Drug Resistance, and Counteracting Progressive Micrometastatic Disease: The Next Frontier of Research

The era of targeted therapies has significantly advanced our understanding of cancer growth and metastasis. Intrinsic or acquired drug resistance remains a major challenge, rendering clinically overt metastatic disease incurable in most patients. This review first examines key clinical trials and their primary outcomes involving targeted therapies in the most common advanced solid tumors, along with the main mechanisms underlying drug resistance. Recently, micrometastatic disease has emerged as a novel focus of investigation aimed at definitively curing advanced solid tumors. Accordingly, this review explores the biology of micrometastases, current challenges in their detection and monitoring, and the main strategies proposed to prevent their progression. The potential roles of nanotechnology and artificial intelligence-driven predictive models are also discussed. Furthermore, we highlight specific characteristics of micrometastatic disease that favor immune modulation, and we evaluate the effectiveness of an immunotherapy regimen that inhibits immune suppression. The lead time provided by serum tumor markers, used experimentally to better track the progression of otherwise undetectable micrometastatic disease, also forms the mechanistic basis for a novel protocol we propose to prevent relapse in high-risk cancer patients. This innovative protocol holds scientific relevance being supported by an appropriate mathematical model and ready for immediate application in clinical practice.