Nasopharyngeal carcinoma: current views on the tumor microenvironment's impact on drug resistance and clinical outcomes

Abstract

The incidence of nasopharyngeal carcinoma (NPC) exhibits significant variations across different ethnic groups and geographical regions, with Southeast Asia and North Africa being endemic areas. Of note, Epstein-Barr virus (EBV) infection is closely associated with almost all of the undifferentiated NPC cases. Over the past three decades, radiation therapy and chemotherapy have formed the cornerstone of NPC treatment. However, recent advancements in immunotherapy have introduced a range of promising approaches for managing NPC. In light of these developments, it has become evident that a deeper understanding of the tumor microenvironment (TME) is crucial. The TME serves a dual function, acting as a promoter of tumorigenesis while also orchestrating immunosuppression, thereby facilitating cancer progression and enabling immune evasion. Consequently, a comprehensive comprehension of the TME and its intricate involvement in the initiation, progression, and metastasis of NPC is imperative for the development of effective anticancer drugs. Moreover, given the complexity of TME and the inter-patient heterogeneity, personalized treatment should be designed to maximize therapeutic efficacy and circumvent drug resistance. This review aims to provide an in-depth exploration of the TME within the context of EBV-induced NPC, with a particular emphasis on its pivotal role in regulating intercellular communication and shaping treatment responses. Additionally, the review offers a concise summary of drug resistance mechanisms and potential strategies for their reversal, specifically in relation to chemoradiation therapy, targeted therapy, and immunotherapy. Furthermore, recent advances in clinical trials pertaining to NPC are also discussed.

Keywords: Drug resistance; Immune escape; Nasopharyngeal carcinoma; Tumor microenvironment.

Fig. 1

Signaling pathways contributed to the progression of nasopharyngeal carcinoma. Initiation of the cell signaling begins with cytokines and growth factors stimulation. The PI3K pathway leads to apoptosis inhibition and tumor cell proliferation. Other signaling pathways including JNK, ERK, JAK, and RAS promote tumor cell proliferation

Fig. 2

Interaction of NPC cells with the tumor microenvironment. EBV-encoded proteins promote tumor development by interacting with tumor-associated cells while limiting the immune infiltration of T cells and NK cells. Immune cells including nature killer (NK) cells, cytotoxic CD8⁺ T cells, M1 macrophage can inhibit NPC tumor growth. In contrast, regulatory T cells (Treg), M2 macrophage, and B cells can promote tumor cell proliferation by inhibiting the activity of CD8⁺ T cells and promote metastasis. Tumor endothelial cells (TEC) and cancer-associated fibroblasts (CAF) can promote tumor proliferation and metastasis by activating survival signaling pathways and producing pro-tumorigenic cytokines. Extracellular matrix acts as a cytokine reservoir at both primary tumor site and metastasis site to support tumor growth

Fig. 3

Drug resistance mechanisms of chemotherapy and immunotherapy. Nasopharyngeal carcinoma cells could develop various drug resistance mechanism against anticancer therapy. A Chemotherapeutic agents exert the anticancer effect through DNA damage and induce cell apoptosis. Upregulation of proteins and miRNAs can inhibit apoptosis and directly confer cell drug resistance phenotype. B Tumor cells can develop drug resistance towards immunotherapy through the interaction with tumor microenvironment. Immune effector cells are able to identify and kill tumor cells through immune infiltration into the tumor site. Granzyme B and D can inhibit the immune infiltration process. Annexin A2 can stimulate Dendritic cells to produce IL-10, which has inhibitory effect on cytotoxic CD8⁺ T cells. Pro-inflammatory cytokines IL-6 and IFN-γ can decrease CD4/CD8 T cell ratio. Cancer-associated fibroblasts (CAF), tumor-associated macrophages (TAM), and myeloid derived suppressor cells (MDSC) can inhibit the activity of immune effector cells. Tumor cells can activate alternative pathways to circumvent PD-1/PD-L1 blockade