The tumor microenvironment is highly complex, and immune escape is currently considered an important hallmark of cancer, largely contributing to tumor progression and metastasis. Named for their capability of killing target cells autonomously, natural killer (NK) cells serve as the main effector cells toward cancer in innate immunity and are highly heterogeneous in the microenvironment. Most current treatment options harnessing the tumor microenvironment focus on T cell-immunity, either by promoting activating signals or suppressing inhibitory ones. The limited success achieved by T cell immunotherapy highlights the importance of developing new-generation immunotherapeutics, for example utilizing previously ignored NK cells. Although tumors also evolve to resist NK cell-induced cytotoxicity, cytokine supplement, blockade of suppressive molecules and genetic engineering of NK cells may overcome such resistance with great promise in both solid and hematological malignancies. In this review, we summarized the fundamental characteristics and recent advances of NK cells within tumor immunometabolic microenvironment, and discussed potential application and limitations of emerging NK cell-based therapeutic strategies in the era of presicion medicine.

Treatment of triple-negative breast cancer (TNBC) remains challenging. Deciphering the orchestration of metabolic pathways in regulating ferroptosis will provide new insights into TNBC therapeutic strategies. Here, we integrated the multiomics data of our large TNBC cohort (n = 465) to develop the ferroptosis atlas. We discovered that TNBCs had heterogeneous phenotypes in ferroptosis-related metabolites and metabolic pathways. The luminal androgen receptor (LAR) subtype of TNBC was characterized by the upregulation of oxidized phosphatidylethanolamines and glutathione metabolism (especially GPX4), which allowed the utilization of GPX4 inhibitors to induce ferroptosis. Furthermore, we verified that GPX4 inhibition not only induced tumor ferroptosis but also enhanced antitumor immunity. The combination of GPX4 inhibitors and anti-PD1 possessed greater therapeutic efficacy than monotherapy. Clinically, higher GPX4 expression correlated with lower cytolytic scores and worse prognosis in immunotherapy cohorts. Collectively, this study demonstrated the ferroptosis landscape of TNBC and revealed an innovative immunotherapy combination strategy for refractory LAR tumors.

Tumors are not only aggregates of malignant cells but also well-organized complex ecosystems. The immunological components within tumors, termed the tumor immune microenvironment (TIME), have long been shown to be strongly related to tumor development, recurrence and metastasis. However, conventional studies that underestimate the potential value of the spatial architecture of the TIME are unable to completely elucidate its complexity. As innovative high-flux and high-dimensional technologies emerge, researchers can more feasibly and accurately detect and depict the spatial architecture of the TIME. These findings have improved our understanding of the complexity and role of the TIME in tumor biology. In this review, we first epitomized some representative emerging technologies in the study of the spatial architecture of the TIME and categorized the description methods used to characterize these structures. Then, we determined the functions of the spatial architecture of the TIME in tumor biology and the effects of the gradient of extracellular nonspecific chemicals (ENSCs) on the TIME. We also discussed the potential clinical value of our understanding of the spatial architectures of the TIME, as well as current limitations and future prospects in this novel field. This review will bring spatial architectures of the TIME, an emerging dimension of tumor ecosystem research, to the attention of more researchers and promote its application in tumor research and clinical practice.

Purpose: The tumor microenvironment has a profound impact on prognosis and immunotherapy. However, the landscape of the triple-negative breast cancer (TNBC) microenvironment has not been fully understood. Experimental Design: Using the largest original multi-omics dataset of TNBC (n = 386), we conducted an extensive immunogenomic analysis to explore the heterogeneity and prognostic significance of the TNBC microenvironment. We further analyzed the potential immune escape mechanisms of TNBC. Results: The TNBC microenvironment phenotypes were classified into three heterogeneous clusters: cluster 1, the "immune-desert" cluster, with low microenvironment cell infiltration; cluster 2, the "innate immune-inactivated" cluster, with resting innate immune cells and nonimmune stromal cells infiltration; and cluster 3, the "immune-inflamed" cluster, with abundant adaptive and innate immune cells infiltration. The clustering result was validated internally with pathological sections and externally with TCGA and METABRIC cohorts. The microenvironment clusters had significant prognostic efficacy. In terms of potential immune escape mechanisms, cluster 1 was characterized by an incapability to attract immune cells, and MYC amplification was correlated with low immune infiltration. In cluster 2, chemotaxis but inactivation of innate immunity and low tumor antigen burden might contribute to immune escape, and mutations in the PI3K-AKT pathway might be correlated with this effect. Cluster 3 featured high expression of immune checkpoint molecules. Conclusions: Our study represents a step towards personalized immunotherapy for TNBC patients. Immune checkpoint inhibitors might be effective for "immune-inflamed" cluster, and the transformation of "cold tumors" into "hot tumors" should be considered for "immune-desert" and "innate immune-inactivated" clusters.