Tumor-associated macrophages (TAM) have key functions in promoting a suppressive tumor immune microenvironment (TIME) and immune evasion, which largely limit treatment effects of immune-checkpoint inhibitors (ICI) in different cancers, including gastric cancer. Dickkopf-1 (DKK1) is associated with tumor progression and has been shown to negatively regulate antitumor immunity, but the impact of DKK1 on the TIME remains incompletely understood. Here, we found that tumoral DKK1 expression is closely associated with worse survival and a suppressive TIME in gastric cancer patients. Results from in vitro coculture assays suggested that DKK1 induces macrophages to become immunosuppressive, thereby inhibiting antitumor responses of CD8+ T cells and natural killer (NK) cells. In vivo DKK1 blockade in syngeneic gastric cancer mouse models reprogramed TAMs to restore the immune activity in the TIME and triggered significant tumor regression. DKK1 blockade also directly reduced the growth of human gastric cancer tumors with high DKK1 expression in a xenograft model. Mechanistically, DKK1 interacted with cytoskeleton-associated protein 4 (CKAP4) on the macrophage surface and activated downstream PI3K–AKT signaling, which contributed to immune suppression. TAM reprogramming by DKK1 blockade also augmented the efficacy of programmed cell death protein-1 (PD-1) blockade in gastric cancer models. Therefore, our study provides novel insights into the role of DKK1 on tumor-intrinsic, innate, and adaptive antitumor immunity modulation and suggests that DKK1 is a promising immunotherapeutic target for enhanced PD-1 blockade therapy in gastric cancer.

Quantum dots (QDs) represent a class of nanoscale wide bandgap semiconductors, and are primarily composed of metals, lipids, or polymers. Their unique electronic and optical properties, which stem from their wide bandgap characteristics, offer significant advantages for early cancer detection and treatment. Metal QDs have already demonstrated therapeutic potential in early tumor imaging and therapy. However, biological toxicity has led to the development of various non-functionalized QDs, such as carbon QDs (CQDs), graphene QDs (GQDs), black phosphorus QDs (BPQDs) and perovskite quantum dots (PQDs). To meet the diverse needs of clinical cancer treatment, functionalized QDs with an array of modifications (lipid, protein, organic, and inorganic) have been further developed. These advancements combine the unique material properties of QDs with the targeted capabilities of biological therapy to effectively kill tumors through photodynamic therapy, chemotherapy, immunotherapy, and other means. In addition to tumor-specific therapy, the fluorescence quantum yield of QDs has gradually increased with technological progress, enabling their significant application in both in vivo and in vitro imaging. This review delves into the role of QDs in the development and improvement of clinical cancer treatments, emphasizing their wide bandgap semiconductor properties.

Semiconductor nanomaterials have emerged as a significant factor in the advancement of tumor immunotherapy. This review discusses the potential of transition metal oxide (TMO) nanomaterials in the realm of anti-tumor immune modulation. These binary inorganic semiconductor compounds possess high electron mobility, extended ductility, and strong stability. Apart from being primary thermistor materials, they also serve as potent agents in enhancing the anti-tumor immunity cycle. The diverse metal oxidation states of TMOs result in a range of electronic properties, from metallicity to wide-bandgap insulating behavior. Notably, titanium oxide, manganese oxide, iron oxide, zinc oxide, and copper oxide have garnered interest due to their presence in tumor tissues and potential therapeutic implications. These nanoparticles (NPs) kickstart the tumor immunity cycle by inducing immunogenic cell death (ICD), prompting the release of ICD and tumor-associated antigens (TAAs) and working in conjunction with various therapies to trigger dendritic cell (DC) maturation, T cell response, and infiltration. Furthermore, they can alter the tumor microenvironment (TME) by reprogramming immunosuppressive tumor-associated macrophages into an inflammatory state, thereby impeding tumor growth. This review aims to bring attention to the research community regarding the diversity and significance of TMOs in the tumor immunity cycle, while also underscoring the potential and challenges associated with using TMOs in tumor immunotherapy.

The Major Histocompatibility Complex Class II molecules (MHC II) have the ability to present tumor antigens to CD4+ T cells, playing a critical role in initiating anti-cancer immunity. Recently, the discovery that MHC II is expressed on many atypical antigen-presenting cells (APCs) has exponentially increased interest in MHC II as a potential target for immunotherapy. Tumor immunotherapies targeting MHC II aim to enhance the sensitivity of tumors to CD4+ T-cell-mediated immune responses by increasing MHC II expression in tumor cells, especially in those traditionally classified as ”cold tumors”-tumors with insufficient T cell infiltration. In clinical studies, MHC II-based personalized vaccines, immune checkpoint blockade (ICB) therapy, and combination immunotherapies have yielded encouraging results.In this review, we describe the intricate cancer immunomodulatory network centered around on MHC II expression on both professional and atypical APCs, highlighting the challenges and opportunities for related immunotherapies. In addition, we analyze how the prediction of MHC II as tumor markers and their specific binding affinities can guide the development of precision medicine to address the unique complexity of each type of cancer.

Tumor-associated macrophages (TAM) have key functions in promoting a suppressive tumor immune microenvironment (TIME) and immune evasion, which largely limit treatment effects of immune-checkpoint inhibitors (ICI) in different cancers, including gastric cancer. Dickkopf-1 (DKK1) is associated with tumor progression and has been shown to negatively regulate antitumor immunity, but the impact of DKK1 on the TIME remains incompletely understood. Here, we found that tumoral DKK1 expression is closely associated with worse survival and a suppressive TIME in gastric cancer patients. Results from in vitro coculture assays suggested that DKK1 induces macrophages to become immunosuppressive, thereby inhibiting antitumor responses of CD8+ T cells and natural killer (NK) cells. In vivo DKK1 blockade in syngeneic gastric cancer mouse models reprogramed TAMs to restore the immune activity in the TIME and triggered significant tumor regression. DKK1 blockade also directly reduced the growth of human gastric cancer tumors with high DKK1 expression in a xenograft model. Mechanistically, DKK1 interacted with cytoskeleton-associated protein 4 (CKAP4) on the macrophage surface and activated downstream PI3K–AKT signaling, which contributed to immune suppression. TAM reprogramming by DKK1 blockade also augmented the efficacy of programmed cell death protein-1 (PD-1) blockade in gastric cancer models. Therefore, our study provides novel insights into the role of DKK1 on tumor-intrinsic, innate, and adaptive antitumor immunity modulation and suggests that DKK1 is a promising immunotherapeutic target for enhanced PD-1 blockade therapy in gastric cancer.