Implication of affective traits in bipolar vulnerability: A study of university students.

Immune checkpoint blockade (ICB) therapy has revolutionized the clinical management of malignant tumors. α-PD-L1, by abrogating tumor-mediated immune suppression and remodeling the antitumor immune microenvironment, has gained regulatory approval for the treatment of a broad spectrum of solid tumors [, , ]. Despite these breakthroughs, clinical evidence indicates that the objective response rate of α-PD-L1 monotherapy remains disappointingly low, ranging from 10% to 30% [, , ]. The intrinsic immunosuppressive nature of the tumor microenvironment (TME) is widely recognized as a pivotal barrier that restricts the therapeutic efficacy of ICB. A hallmark of cancer is metabolic reprogramming, wherein tumor cells predominantly rely on glycolysis for energy production, even under normoxic conditions—a phenomenon known as the Warburg effect [,]. This metabolic shift drives the aberrant accumulation of lactate within the TME. Excessive lactate not only establishes an acidic extracellular environment but also stabilizes the expression of hypoxia-inducible factor-1α (HIF-1α) by inhibiting the activity of prolyl hydroxylases (PHDs) [, , ]. This stabilization further transcriptionally upregulates PD-L1 expression, thereby directly impairing the cytolytic function of cytotoxic T lymphocytes (CTLs). To reverse this immunosuppressive cycle, lactate oxidase (LOX) has emerged as a compelling therapeutic enzyme due to its unique capacity to specifically catalyze lactate catabolism []. LOX mediates the oxidative breakdown of lactate into pyruvate and hydrogen peroxide (HO), while simultaneously consuming protons (H) in the TME. This dual enzymatic modulation effectively scavenges excess lactate and mitigates the acidic TME, thereby abrogating the direct suppression of CTLs. Concomitantly, LOX-mediated metabolism compromises HIF-1α stability and downregulates PD-L1 expression. These coordinated effects synergistically release the ‘immune checkpoint’ constraint on CTLs and disrupt the vicious cycle of lactate-driven immunosuppression in the TME.