Impact of the Tumor Microenvironment on Progression and Treatment Response in Lymphoma and Chronic Lymphocytic Leukemia: A Systematic Review of the Literature.

Abstract

Introduction: The tumor microenvironment (TME) plays a critical role in the progression of lymphomas and chronic lymphocytic leukemia (CLL). Comprising immune cells, cytokines, growth factors, and the extracellular matrix, it modulates therapeutic resistance and tumor aggressiveness. Key elements such as Tregs and TAMs induce immunosuppression, while cytokines like IL-6 promote malignant cell proliferation and survival.

Objective: To synthesize evidence regarding the influence of the TME on the progression and treatment response in lymphoma and CLL, identifying knowledge gaps and potential therapeutic targets.

Methods: A systematic review was conducted following PRISMA guidelines, including 17 studies published between 2000-2024 on the TME in lymphoma and CLL. Primary outcomes included overall survival (OS), progression-free survival (PFS), and treatment response rates. Searches included databases such as PubMed, Scopus, and Cochrane.

Results: Elevated IL-6 levels were associated with worse OS in aggressive lymphomas (mean OS 43.3 months in IL-6 positive patients vs. 96.0 months in negative, p < 0.001). A high proportion of Tregs in the TME correlated with shorter PFS (53% at 5 years vs. 72%, p = 0.013). In CLL, treatment with BTK inhibitors favorably modified the Th2/Th1 ratio (p < 0.002), improving clinical responses.

Discussion: The findings confirm the relevance of the TME as a determinant of clinical and prognostic heterogeneity. IL-6 and Tregs emerge as key biomarkers and therapeutic targets. Strategies aimed at reversing immunosuppression could optimize clinical outcomes; however, methodological limitations persist, such as heterogeneity in TME characterization methods.