LAPTM4B in tumor immune evasion: lysosomal autophagy, metabolic adaptation, and therapeutic resistance

Abstract

Tumor immune evasion is shaped not only by canonical immune checkpoints but also by lysosomal stress adaptation, autophagy, metabolic remodeling, and therapy-induced survival programs within malignant cells. Lysosomal-associated protein transmembrane 4 beta (LAPTM4B), an oncogenic lysosomal transmembrane protein, has emerged as a candidate regulator of these interconnected processes through its roles in lysosomal homeostasis, autophagic flux, receptor trafficking, metabolic adaptation, and therapeutic resistance. Experimental studies support important roles for LAPTM4B in lysosomal homeostasis, autophagic regulation, and multiple forms of therapy resistance. Additional evidence links autophagy-dependent stress adaptation to HIF-1α stabilization, glycolytic remodeling, lactate accumulation, and immunoregulatory changes within the TME. On the basis of these direct and indirect observations, this review proposes a conceptual model in which LAPTM4B may function as a context-dependent organizing node that helps couple lysosomal stress tolerance, metabolic adaptation, and immune escape in selected tumor settings. In this framework, LAPTM4B may contribute to sustained autophagic flux under stress, support metabolic conditions compatible with aerobic glycolysis, and potentially facilitate downstream immunosuppressive processes, including lactate-associated microenvironmental remodeling. We also review structural heterogeneity of LAPTM4B, clinical associations across multiple malignancies, multidrug-resistance mechanisms, and emerging evidence for EGFR-TKI escape mediated by LAPTM4B-dependent stabilization of ATP1A1 in non-small cell lung cancer. Current evidence supports LAPTM4B as an important regulator of lysosomal adaptation and therapy resistance, whereas its broader role in tumor immune evasion remains a testable model rather than an experimentally settled mechanism. We therefore present the autophagy-metabolism-immunity axis as a layered framework: experimentally supported in selected tumor contexts, indirectly supported by related metabolic and immune observations, and hypothesis-generating where direct causal evidence remains absent.