Non-Hodgkin’s lymphoma (NHL), particularly its aggressive subtype diffuse large B-cell lymphoma (DLBCL), remains a significant clinical challenge due to frequent relapse and resistance to conventional therapies. Recent research has increasingly focused on the tumor microenvironment (TME) — the complex ecosystem surrounding tumor cells — as a promising frontier for discovering new therapeutic targets. The TME is composed of various cell types, signaling molecules, metabolic factors, and structural components that collectively influence tumor growth, immune evasion, and treatment response.
The TME in NHL is not merely a passive backdrop but an active participant in disease progression. It includes immune cells such as T cells, regulatory T cells (Tregs), macrophages, dendritic cells, and cancer-associated fibroblasts (CAFs), as well as extracellular matrix components and soluble factors like cytokines and chemokines. These elements create a dynamic environment that can suppress anti-tumor immunity and promote tumor survival. For example, immunosuppressive cells and cytokines within the TME can exhaust the function of cytotoxic T cells, which are critical for attacking lymphoma cells. Additionally, metabolic competition in the TME deprives immune cells of essential nutrients, further weakening their ability to control tumor growth.
One of the key mechanisms by which the TME influences NHL is through metabolic remodeling. Tumor cells and immune cells compete for glucose and other metabolites, but the tumor often creates a nutrient-poor, hypoxic environment that impairs immune cell function. This metabolic stress can lead to mitochondrial dysfunction in T cells, reducing their cytotoxicity and proliferation. Understanding these metabolic interactions opens the door to therapies that can reprogram the metabolism of immune cells or modify the TME to restore immune function. For instance, combining metabolic regulatory drugs with CAR-T cell therapies — where a patient’s T cells are engineered to better target lymphoma cells — shows promise in overcoming the suppressive effects of the TME and enhancing treatment efficacy.
Epigenetic reprogramming within the TME also plays a crucial role in NHL progression. Epigenetic changes such as DNA methylation and histone modifications can alter gene expression patterns in both tumor and immune cells, facilitating immune evasion and tumor growth. These modifications are reversible, making them attractive targets for novel therapies. Drugs that reverse epigenetic dysregulation can potentially restore immune surveillance by reactivating silenced genes involved in immune responses. Advances in genomics and single-cell analyses have revealed how these epigenetic alterations shape the interactions between lymphoma cells and their microenvironment, guiding the development of precision medicine approaches that combine epigenetic therapies with immune modulation.
Another important aspect of the TME is the physical and chemical barriers it creates to immune cell infiltration. Cancer-associated fibroblasts contribute to the formation of dense stromal barriers through collagen production and fibrosis, physically blocking cytotoxic T cells and other immune effectors from reaching tumor cells. Moreover, tumors can suppress the expression of chemokines, molecules that normally attract immune cells, further preventing immune infiltration. These mechanisms of immune exclusion are critical hurdles in the effective immunotherapy of NHL. Targeting CAFs or restoring chemokine signaling pathways could improve immune cell access to tumors and enhance the effectiveness of immunotherapies.
Cytokines within the TME also influence NHL outcomes. Proinflammatory cytokines like interleukin-6 (IL-6) have been correlated with poor prognosis in aggressive lymphomas. IL-6 can promote tumor growth and survival, as well as contribute to the immunosuppressive milieu. Targeting cytokine signaling pathways represents another strategy to modulate the TME and improve patient outcomes.
Single-cell RNA sequencing technologies have recently illuminated the intricate cellular interactions within the NHL TME, revealing heterogeneity among tumor and immune cells and identifying novel cellular subsets and signaling pathways involved in tumor progression. This high-resolution insight enables the identification of new molecular targets and the design of therapies tailored to disrup
