The Emerging Mechanisms and Therapeutic Potentials of Dendritic Cells in NSCLC

Abstract

Non-small-cell lung cancer (NSCLC) is the predominant subtype of lung cancer. Despite the demonstrated effectiveness of established treatments such as radiotherapy, chemotherapy, and immunotherapy, the prognosis for patients with advanced NSCLC remains poor. Dendritic cells (DCs), the most potent antigen-presenting cells (APCs), play a crucial role in the tumor microenvironment (TME) of NSCLC. This review explores the classification and biological functions of DCs, highlighting the specific molecular pathways and external factors that influence their maturation and function in NSCLC, which is novel in this review. Moreover, we discuss the potential therapeutic applications of DCs in the management of NSCLC, presenting novel possibilities for future treatments.

Keywords: dendritic cells; maturation; non-small-cell lung cancer; treatment.

Figure 1

The whole process of differentiation, maturation and function of DCs. Hematopoietic stem cells in bone marrow undergo differentiation into pre-DCs under the influence of cytokines. Subsequently, pre-DCs further transform into imDCs upon stimulation by cytokines and antigens. imDCs possess a high capacity for antigen uptake and migrate through the blood and lymph circulation. During the migration process, the surface molecules and cell morphology of imDCs changed and gradually transformed into mDCs. mDCs highly expressed MHC, CD80, CD86, CD40, CD54 and CCR7. In secondary lymphoid organs, mDCs present MHC class II-peptide complexes to naive T cells, prompting their differentiation into effector T cells.

Figure 2

Factors affecting DC maturation and function in NSCLC. (A) The activation of NF-κB, STAT3 and MAPK pathways promotes the maturation of DCs. NF-κB signaling pathway can be activated by the elevation of TLR4, MyD88, and NF-κB levels. SHP-1 binds to STAT3 can mediate its dephosphorylation. MAPK signaling pathway can be activated through the phosphorylation of JNK, ERK, and p38 MAPK. (B) Glycolysis promotes STING signal-dependent tumor-infiltrating DC activity in NSCLC, which accelerates PKM2 and HIF-1α-mediated glycolysis and establishes a positive feedback loop. (C) LncMALAT1 can be transferred to DCs via exosomes released by NSCLC tumor cells. Elevated expression of LncMALAT1 has been shown to inhibit the maturation phenotype and function of DCs in NSCLC. (D) The release of tumor-derived factors such as VEGF, TGF-β, and IL-10 inhibits DC maturation, while the release of CCL19 and TNF-α promotes DC migration and maturation. (E) Several pathways can regulate M2 macrophage polarization. In THP-1 cells, reduced NOD2 expression and inhibited NF-κB pathway promote M2 macrophages polarization. In CD11b⁺ cells, high STAT6 expression promotes IL-4 secretion, leading to M2 polarization. In NSCLC cells, abundant NOX4 expression activates the PI3K/AKT signaling pathway, causing M2 polarization.