Unmasking the role of tumor microenvironment in the advanced stage of cancer treatment to mitigate risks during chemotherapy.

The complexity of the tumor microenvironment in advanced-stage cancer critically diminishes the activity of chemotherapy, often reducing its efficacy to a point where the inherent risks become clinically unwarranted. This review "unmasks" the tumor microenvironment as a sophisticated barrier system driven primarily by hypoxia, i.e. severe oxygen deprivation. Hypoxia stabilizes master-regulators, including hypoxia-inducible factor-1α, which actively induce multidrug resistance. Specifically, hypoxia-inducible factor-1α orchestrates drug expulsion from the cancer cell via efflux pumps and enhances cellular repair of drug-induced DNA damage, functionally neutralizing cytotoxic agents. This resistance is compounded by tumor heterogeneity, which promotes the selection of aggressive, drug-evading subclones, and by hypoxia-induced degradation of the major histocompatibility complex class I, rendering cancer cells invisible to the immune system. Translational challenges, such as the mixed efficacy of hypoxia-activated prodrugs, highlight the urgent need for robust diagnostics to accurately verify tumor microenvironment conditions. To restore therapeutic efficacy and mitigate the risks of ineffective treatments, a paradigm shift is necessary: integrating tumor microenvironment-targeted agents (such as hypoxia-inducible factor-2α inhibitors) with adaptive dosing strategies guided by real-time molecular monitoring, including liquid biopsies and hypoxia-PET imaging. This integrated strategy is essential for achieving durable patient outcomes.