Tumor-associated macrophages (TAMs) have key functions in promoting a suppressive tumor immune microenvironment (TIME) and immune evasion, which largely limit treatment effects of immune checkpoint inhibitors (ICIs) in different cancers, including gastric cancer (GC). Dickkopf-1 (DKK1) associates with tumor progression and has been shown to negatively regulate anti-tumor immunity, but the impact of DKK1 on the TIME remains incompletely understood. Here, we found that tumoral DKK1 expression closely associated with worse survival and a suppressive TIME in GC patients. Results from in vitro co-culture assays suggested that DKK1 induces macrophages to become immunosuppressive, thereby inhibiting anti-tumor responses of CD8+ T cells and natural killer (NK) cells. In vivo DKK1 blockade in syngeneic GC mouse models reprogramed TAMs to restore the immune activity in the TIME and triggered significant tumor regression. DKK1 blockade also directly reduced growth of human GC 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 GC models. Therefore, our study provides novel insights into the role of DKK1 on tumor-intrinsic, innate, and adaptive anti-tumor immunity modulation and suggests that DKK1 is a promising immunotherapeutic target for enhanced PD-1 blockade therapy in GC.

Cold tumor is one of the most refractory tumors due to its low immunogenicity and absence of T cell infiltration. The immunotherapeutic effect of near‐infrared (NIR) responsive nanomaterials on tumors is far from satisfactory. Herein, ultrasmall γ‐MnO2 nanodots are anchored on the intrinsic metallic Ti3C2(OH)2, modified with bovine serum albumin, to realize a Schottky heterojunction (labeled as TC‐MnO2@BSA), which can be utilized to reshape the cold tumor microenvironment (TME) through in situ vaccine‐like antitumor effect. The Schottky heterojunction endows TC‐MnO2@BSA with improved photothermal conversion and reactive oxygen species (ROS) generation. Excess ROS and heat lead to tumor immunogenic death (ICD) and abundant damaged double‐strain DNA releasing into TME, coordinated with TC‐MnO2@BSA‐derived Mn2+, magnifying the cGAS‐STING signaling pathway, eventually promoting antigen presentation of dendritic cells and infiltration of T cells. Such a NIR‐activated nanovaccine can achieve complete ablation of tumors while robust activating systemic antitumor immune response. Furthermore, it inhibits the growth of abscopal tumors through dramatically “heating” their cold TME. This work introduces a universal strategy to magnify the photothermal and immune adjuvant effect through the gain of Schottky heterostructure, as a novel paradigm to construct the multifunctional in situ nanovaccine.

Therapies mobilizing host immunity against cancer cells have profoundly improved prognosis of cancer patients. However, efficacy of immunotherapies depends on local immune conditions. The “cold” tumor, which is characterized by lacking inflamed T cells, is insensitive to immunotherapy. Current strategies of improving the “cold” tumor microenvironment are far from satisfying. Nanoparticle-based therapies provide novel inspiration in firing up the tumor microenvironment. In this review, we presented progress and limitations of conventional immunotherapies. Then, we enumerate advantages of nanoparticle-based therapies in remodeling the “cold” tumor microenvironment. Finally, we discuss the prospect of nanoparticle-based therapies in clinical application.

Supplementary Data from DKK1 Promotes Tumor Immune Evasion and Impedes Anti–PD-1 Treatment by Inducing Immunosuppressive Macrophages in Gastric Cancer

<div>Abstract<p>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 <i>in vitro</i> coculture assays suggested that DKK1 induces macrophages to become immunosuppressive, thereby inhibiting antitumor responses of CD8⁺ T cells and natural killer (NK) cells. <i>In vivo</i> 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.</p></div>