Hypoxia in lymphoma: Mechanistic remodeling of the tumor microenvironment, disease progression and therapeutic resistance (Review)

Hypoxia is increasingly recognized as a determinant of tumor behavior across multiple malignancies; yet, its role in lymphoma remains incompletely defined and is frequently generalized across biologically distinct disease entities. In lymphoma, hypoxia is not merely a consequence of rapid tumor expansion and abnormal vascularization, but an active driver of tumor microenvironment remodeling, metabolic adaptation, immune escape, angiogenesis and therapeutic resistance. Emerging evidence suggests that hypoxia‑inducible signaling, lactate accumulation, adenosine metabolism, macrophage polarization and altered mitochondrial fitness collectively shape lymphoma progression and treatment response. However, the strength of evidence varies markedly by lymphoma subtype and a notable proportion of mechanistic assumptions is still derived from solid tumors or non‑lymphoma systems. The present review provides a structured summary of current knowledge regarding hypoxia in lymphoma, with emphasis on microenvironmental regulation, disease progression and resistance to chemotherapy, radiotherapy, antibody‑based therapy and cellular immunotherapy. Particular attention is given to the distinction between direct lymphoma‑derived evidence and indirect extrapolation. The present review also highlights major unresolved questions, including subtype‑specific heterogeneity, differences between acute and chronic hypoxia, and the need for clinically actionable biomarkers and combination strategies. A more rigorous understanding of hypoxia in lymphoma may improve biological stratification and identify context‑specific therapeutic vulnerabilities.