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The Role of Ladder Combination Therapy in the Treatment of Advanced Tumors in the Tunnel Nanotube Pathway
The treatment of advanced tumors has entered a new era of multimodal synergy. Tunneling Nanotubes (TNTs), as a critical pathway for intercellular substance and signal transmission, play a central regulatory role in tumor progression, drug resistance, and immune evasion. The stepwise combination therapy, based on tumor heterogeneity and disease progression patterns, employs a progressive strategy of “targeted blockade-precision delivery-immune activation” to specifically regulate the structural function and signal transmission of the TNTs pathway. This article systematically elucidates the biological characteristics of TNTs and their pathological roles in the advanced tumor microenvironment. It provides an in-depth analysis of how stepwise combination therapy exerts therapeutic effects through mechanisms such as inhibiting TNTs formation, disrupting TNTs-mediated drug resistance delivery, and enhancing immune responses via TNTs. The review also summarizes progress in preclinical studies and early clinical applications of this strategy. Studies demonstrate that stepwise combination therapy can suppress TNTs formation by regulating signaling pathways like Fyn/ROCK/p-paxillin, while leveraging TNTs’ transport properties to achieve drug-targeted enrichment. Compared to single-treatment modalities, this approach increases objective response rates in advanced tumors by over 30%. Finally, the study explores technical bottlenecks and translational prospects in this field, providing new perspectives and experimental evidence for precision treatment of advanced tumors.
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