Background: Our previous work showed that the anti-TGF-β/PD-L1 bispecific antibody YM101 effectively overcame anti-PD-L1 resistance in immune-excluded tumor models. However, in immune-desert models, the efficacy of YM101 was limited. Bivalent manganese (Mn²⁺) is identified as a natural stimulator of interferon genes (STING) agonist, which might enhance cancer antigen presentation and improve the therapeutic effect of YM101. Methods: The effect of Mn²⁺ on STING pathway was validated by western blotting and enzyme-linked immunosorbent assay. Dendritic cell (DC) maturation was measured by flow cytometry. The synergistic effect between Mn²⁺ and YM101 in vitro was determined by one-way mixed lymphocyte reaction, CFSE dilution assay, and cytokine detection. The in vivo antitumor effect of Mn²⁺ plus YM101 therapy was assessed in CT26, EMT-6, H22, and B16 tumor models. Flow cytometry, RNA-seq, and immunofluorescent staining were adopted to investigate the alterations in the tumor microenvironment. Results: Mn²⁺ could activate STING pathway and promote the maturation of human and murine DC. The results of one-way mixed lymphocyte reaction showed that Mn²⁺ synergized YM101 in T cell activation. Moreover, in multiple syngeneic murine tumor models, Mn²⁺ plus YM101 therapy exhibited a durable antitumor effect and prolonged the survival of tumor-bearing mice. Relative to YM101 monotherapy and Mn²⁺ plus anti-PD-L1 therapy, Mn²⁺ plus YM101 treatment had a more powerful antitumor effect and a broader antitumor spectrum. Mechanistically, Mn²⁺ plus YM101 strategy simultaneously regulated multiple components in the antitumor immunity and drove the shift from immune-excluded or immune-desert to immune-inflamed tumors. The investigation in the TME indicated Mn²⁺ plus YM101 strategy activated innate and adaptive immunity, enhanced cancer antigen presentation, and upregulated the density and function of tumor-infiltrating lymphocytes. This normalized TME and reinvigorated antitumor immunity contributed to the superior antitumor effect of the combination therapy. Conclusion: Combining Mn²⁺ with YM101 has a synergistic antitumor effect, effectively controlling tumor growth and prolonging the survival of tumor-bearing mice. This novel cocktail strategy has the potential to be a universal regimen for inflamed and non-inflamed tumors.

Immunotherapy, especially anti-programmed cell death protein 1/programmed cell death ligand 1 (PD-1/PD-L1) treatment has significantly improved the survival of non-small cell lung cancer (NSCLC) patients. However, the overall response rate remains unsatisfactory. Many factors affect the outcome of anti-PD-1/PD-L1 treatment, such as PD-L1 expression level, tumor-infiltrating lymphocytes (TILs), tumor mutation burden (TMB), neoantigens, and driver gene mutations. Further exploration of biomarkers would be favorable for the best selection of patients and precisely predict the efficacy of anti-PD-1/PD-L1 treatment. In this review, we summarized the latest advances in this field, and discussed the potential applications of these laboratory findings in the clinic.

Transcriptional heterogeneity of tumor-associated macrophages (TAMs) has been investigated in individual cancers, but the extent to which these states transcend tumor types and represent a general feature of cancer remains unclear. We performed pan-cancer single-cell RNA sequencing analysis across nine cancer types and identified distinct monocyte/TAM composition patterns. Using spatial analysis from clinical study tissues, we assessed TAM functions in shaping the tumor microenvironment (TME) and influencing immunotherapy. Two specific TAM clusters (pro-inflammatory and pro-tumor) and four TME subtypes showed distinct immunological features, genomic profiles, immunotherapy responses, and cancer prognosis. Pro-inflammatory TAMs resided in immune-enriched niches with exhausted CD8+ T cells, while pro-tumor TAMs were restricted to niches associated with a T-cell-excluded phenotype and hypoxia. We developed a machine learning model to predict immune checkpoint blockade response by integrating TAMs and clinical data. Our study comprehensively characterizes the common features of TAMs and highlights their interaction with the TME.

Microvesicles are extracellular vesicles with diameter ranging from 100 to 1000 nm that are secreted by tumor cells or other cells in the tumor microenvironment. A growing number of studies demonstrate that tumor-derived microvesicles are involved in tumor initiation and progression, as well as drug resistance. In addition, tumor-derived microvesicles carry a variety of immunogenic molecules and inhibit tumor response to immunotherapy; therefore, they can be exploited for use in tumor vaccines. Moreover, because of their high stability, tumor-derived microvesicles extracted from body fluids can be used as biomarkers for cancer diagnosis or assessment of prognosis. Tumor-derived microvesicles can also be deployed to reverse drug resistance of tumor regenerative cells, or to deliver chemotherapeutic drugs and oncolytic adenovirus for the treatment of cancer patients. This review summarizes the general characteristics of tumor-derived microvesicles, focusing on their biological characteristics, their involvement in tumor progression, and their clinical applications.

Introduction: On the basis of the recently recognized potential of hematopoietic stem cells (HSCs) to give rise to hepatocytes, we have assessed the potential of granulocyte colony-stimulating factor (G-CSF)-mobilized bone marrow-derived CD34⁺ HSCs to contribute to faster recovery and promote regeneration process after acute liver injury by radiation. Methods: G-CSF-mobilized CD34⁺ HSCs (1 × 10⁵ cells per mouse) were injected via tail vein in the irradiated femal nonobese diabetic/severe combined immunodeficient mice. Irradiated control animals received only saline infusion. Results: The mobilized CD34⁺ HSCs significantly ameliorated radiation-induced liver damage. In the liver of recipient mice killed 21 days after irradiation, human albumin⁺ Y-chromosome⁺ hepatocyte-like cells, or human cytokeratin⁺ Y-chromosome⁺ hepatocyte-like cells formed cords of hepatocytes, occupied ~30% of the 4-μm section surrounding portal tracts. Furthermore, human-specific albumin mRNA expressed in the liver and human albumin was detected in the serum only in the CD34⁺ HSC-treated mice. Conclusions: Treatment with G-CSF-mobilized CD34⁺ HSCs from bone marrow into peripheral blood could significantly promote tissue reparation after acute liver injury by radiation in mice, possibly by the ability of CD34⁺ HSCs to generate hepatocytes. So mobilization of CD34⁺ HSCs might offer a novel therapeutic approach for the treatment of radiation-induced complications after radiotherapy or other acute liver diseases in humans.

Cancer stem cells (CSCs) actively reprogram their tumor microenvironment (TME) to sustain a supportive niche, which may have a dramatic impact on prognosis and immunotherapy. However, our knowledge of the landscape of the gastric cancer stem-like cell (GCSC) microenvironment needs to be further improved. A multi-step process of machine learning approaches was performed to develop and validate the prognostic and predictive potential of the GCSC-related score (GCScore). The high GCScore subgroup was not only associated with stem cell characteristics, but also with a potential immune escape mechanism. Furthermore, we experimentally demonstrated the upregulated infiltration of CD206⁺ tumor-associated macrophages (TAMs) in the invasive margin region, which in turn maintained the stem cell properties of tumor cells. Finally, we proposed that the GCScore showed a robust capacity for prediction for immunotherapy, and investigated potential therapeutic targets and compounds for patients with a high GCScore. The results indicate that the proposed GCScore can be a promising predictor of prognosis and responses to immunotherapy, which provides new strategies for the precision treatment of GCSCs.