Nanomedicine design strategy for preferential elimination of cancer stem cells by targeted HIF-Warburg-immune evasion axis: Systematic review.

Abstract

Cancer stem cells (CSCs) drive tumor recurrence, metastasis, and therapeutic resistance.Rather than exhibiting a uniform glycolytic phenotype, CSCs occupy tumor- and state-dependent metabolic configurations ranging from glycolysisdominant to oxidative phosphorylation（OXPHOS）-dependent and hybrid states. In hypoxic and hypoxia-inducible factor-1α（HIF-1α）-active CSC subpopulations, aerobic glycolysis can support stemness, treatment resistance, and immune evasion by increasing glucose consumption, lactate production, and microenvironmental acidification. Accordingly, the HIF-Warburg axis represents an actionable but context-dependent metabolic vulnerability. This review systematically examines nanodrug design strategies targeting the HIF-Warburg axis, spanning four regulatory levels: (1) Direct inhibition of HIF-1α expression via nanocarriers delivering siRNA or oxygen-releasing particles; (2) Inhibition of glycolysis through nanoscale inhibitors targeting HK2, LDHA, and PDK1; (3) Substrate deprivation by targeting GLUT1 or employing glucose oxidase; and (4) Lactate neutralization and pH-responsive nanosystems to reverse the acidic microenvironment, reactivate immune responses, and achieve metabolic-immune synergistic therapy. This review synthesizes interactions among CSCs, the Warburg effect, HIF-1α signaling, and immune evasion mechanisms, and highlights emerging nanotherapeutic strategies that exploit these vulnerabilities to improve cancer treatment outcomes, offering significant promise for advancing precision cancer therapy.