Transcatheter arterial chemoembolization (TACE) is the first-line therapy for hepatocellular carcinoma (HCC). However, the exacerbated hypoxia microenvironment induces tumor relapse and metastasis post-TACE. Here, temperature-sensitive block polymer complexed with polyphosphate-cisplatin (Pt-P@PND) was prepared for the enhancement of tumor artery embolization by coagulation activation. After supra-selective infusion into the tumor vessels, Pt-P@PND nanogels performed efficient embolization of tumor arteries by sol-gel transition at body temperature. Meanwhile, coagulation cascade was evoked to form blood clots in the peripheral arteries inaccessible to the nanogels by released PolyP. The blood clots-filled hydrogel networks composed of gel and clots showed a denser structure and higher modulus, thereby achieving long-term embolization of all levels of tumor arteries. Pt-P@PND nanogels efficiently inhibited tumor growth and reduced the expression of HIF-1α, VEGF, CD31, and MMP-9 on VX2 tumor-bearing rabbit model. The released Nitro-Pt stimulated the immunogenic cell death of tumor cells, thus enhancing the antitumor immune response to suppress tumor relapse and metastasis post-TACE. It is hoped that Pt-P@PND nanogels can be developed as a promising embolic agent with procoagulant activity for enhancing the antitumor immune response through a combination of embolism, coagulation, and chemotherapy. STATEMENT OF SIGNIFICANCE: Clinical embolic agents, such as Lipiodol and polyvinyl alcohol (PVA) microspheres, are limited by their rapid elimination or larger size, thus lead to incomplete embolization of trans-catheter arterial chemoembolization (TACE). Herein, temperature-sensitive Pt-P@PND nanogels were developed to achieve long-term embolization of all levels of tumor arteries by gel/clot generation. The released Nitro-Pt induced immunogenic cell death in tumor cells, which improved the antitumor immune microenvironment by the maturation of DCs and lymphocytic infiltration. Pt-P@PND nanogels successfully inhibited tumor growth and activated an antitumor immune response to curb the recurrence and metastasis of residual tumor cells both in VX2 tumor-bearing rabbit model and 4T1 tumor-bearing mouse model. These findings suggested that Pt-P@PND could be developed as an ideal embolic agent for clinical TACE treatment.

Immune checkpoint blockade (ICB) has significantly improved the prognosis of patients with cancer, although the majority of such patients achieve low response rates; consequently, new therapeutic approaches are urgently needed. The upregulation of sialic acid-containing glycans is a common characteristic of cancer-related glycosylation, which drives disease progression and immune escape via numerous pathways. Herein, the development of self-assembled core-shell nanoscale coordination polymer nanoparticles loaded with a sialyltransferase inhibitor, referred to as NCP-STI which effectively stripped diverse sialoglycans from cancer cells, providing an antibody-independent pattern to disrupt the emerging Siglec-sialic acid glyco-immune checkpoint is reported. Furthermore, NCP-STI inhibits sialylation of the concentrated nucleoside transporter 1 (CNT1), promotes the intracellular accumulation of anticancer agent gemcitabine (Gem), and enhances Gem-induced immunogenic cell death (ICD). As a result, the combination of NCP-STI and Gem (NCP-STI/Gem) evokes a robust antitumor immune response and exhibits superior efficacy in restraining the growth of multiple murine tumors and pulmonary metastasis. Collectively, the findings demonstrate a novel form of small molecule-based chemo-immunotherapy approach which features sialic acids blockade that enables cooperative effects of cancer cell chemosensitivity and antitumor immune responses for cancer treatment.

BACKGROUND: TMPRSS2, a key molecule for SARS-CoV-2 invading human host cells, has an association with cancer. However, its association with lung cancer remains insufficiently unexplored.
METHODS: In five bulk transcriptomics datasets, one single-cell RNA sequencing (scRNA-seq) dataset and one proteomics dataset for lung adenocarcinoma (LUAD), we explored associations between TMPRSS2 expression and immune signatures, tumor progression phenotypes, genomic features, and clinical prognosis in LUAD by the bioinformatics approach. Furthermore, we performed experimental validation of the bioinformatics findings.
RESULTS: TMPRSS2 expression levels correlated negatively with the enrichment levels of both immune-stimulatory and immune-inhibitory signatures, while they correlated positively with the ratios of immune-stimulatory/immune-inhibitory signatures. It indicated that TMPRSS2 levels had a stronger negative correlation with immune-inhibitory than with immune-stimulatory signatures. TMPRSS2 downregulation correlated with increased proliferation, stemness, genomic instability, tumor progression, and worse survival in LUAD. We further validated that TMPRSS2 was downregulated with tumor progression in the LUAD cohort we collected from Jiangsu Cancer Hospital, China. In vitro and in vivo experiments verified the association of TMPRSS2 deficiency with increased tumor cell proliferation and invasion and antitumor immunity in LUAD. Moreover, in vivo experiments demonstrated that TMPRSS2-knockdown tumors were more sensitive to BMS-1, an inhibitor of PD-1/PD-L1.
CONCLUSIONS: TMPRSS2 is a tumor suppressor, while its downregulation is a positive biomarker of immunotherapy in LUAD. Our data provide a potential link between lung cancer and pneumonia caused by SARS-CoV-2 infection.

The dense extracellular matrix (ECM) in solid tumors, contributed by cancer-associated fibroblasts (CAFs), hinders penetration of drugs and diminishes their therapeutic outcomes. A sequential treatment strategy of remodeling the ECM via a CAF modifier (dasatinib, DAS) is proposed to promote penetration of an immunogenic cell death (ICD) inducer (epirubicin, Epi) via apoptotic vesicles, ultimately enhancing the treatment efficacy against breast cancer. Dendritic poly(oligo(ethylene glycol) methyl ether methacrylate) (POEGMA)-based nanomedicines (poly[OEGMA-Dendron(G2)-Gly-Phe-Leu-Gly-DAS] (P-DAS) and poly[OEGMA-Dendron(G2)-hydrazone-Epi] (P-Epi)) are developed for sequential delivery of DAS and Epi, respectively. P-DAS reprograms CAFs to reduce collagen by downregulating collagen anabolism and energy metabolism, thereby reducing the ECM deposition. The regulated ECM can enhance tumor penetration of P-Epi to strengthen its ICD effect, leading to an amplified antitumor immune response. In breast cancer-bearing mice, this approach alleviates the ECM barrier, resulting in reduced tumor burden and increased cytotoxic T lymphocyte infiltration, and more encouragingly, synergizes effectively with anti-programmed cell death 1 (PD-1) therapy, significantly inhibiting tumor growth and preventing lung metastasis. Furthermore, systemic toxicity is barely detectable after sequential treatment with P-DAS and P-Epi. This approach opens a new avenue for treating desmoplastic tumors by metabolically targeting CAFs to overcome the ECM barrier.

BACKGROUND: The combination of radiotherapy and immunotherapy (immunoradiotherapy) has been increasingly used for treating a wide range of cancers. However, some tumors are resistant to immunoradiotherapy. We have previously shown that MER proto-oncogene tyrosine kinase (MerTK) expressed on macrophages mediates resistance to immunoradiotherapy. We therefore sought to develop therapeutics that can mitigate the negative impact of MerTK. We designed and developed a MerTK specific antisense oligonucleotide (ASO) and characterized its effects on eliciting an anti-tumor immune response in mice.
METHODS: 344SQR cells were injected into the right legs on day 0 and the left legs on day 4 of 8-12 weeks old female 129sv/ev mice to establish primary and secondary tumors, respectively. Radiation at a dose of 12 Gy was given to the primary tumors on days 8, 9, and 10. Mice received either anti-PD-1, anti-CTLA-4 or/and MerTK ASO starting from day 1 post tumor implantation. The composition of the tumor microenvironment and the level of MerTK on macrophages in the tumor were evaluted by flow cytometry. The expression of immune-related genes was investigated with NanoString. Lastly, the impact of MerTK ASO on the structure of the eye was histologically evaluated.
RESULTS: Remarkably, the addition of MerTK ASO to XRT+anti-PD1 and XRT+anti-CTLA4 profoundly slowed the growth of both primary and secondary tumors and significantly extended survival. The ASO significantly reduced the expression of MerTK in tumor-associated macrophages (TAMs), reprograming their phenotype from M2 to M1. In addition, MerTK ASO increased the percentage of Granzyme B+ CD8+ T cells in the secondary tumors when combined with XRT+anti-CTLA4. NanoString results demonstrated that the MerTK ASO favorably modulated immune-related genes for promoting antitumor immune response in secondary tumors. Importantly, histological analysis of eye tissues demonstrated that unlike small molecules, the MerTK ASO did not produce any detectable pathology in the eyes.
CONCLUSIONS: The MerTK ASO can significantly downregulate the expression of MerTK on TAMs, thereby promoting antitumor immune response. The combination of MerTK ASO with immunoradiotherapy can safely and significantly slow tumor growth and improve survival.

Transarterial chemoembolization (TACE) may prolong the survival of patients with hepatocellular carcinoma (HCC); however, its efficacy is limited due to the high rate of incomplete embolization. Hypoxia after embolization can cause a series of changes in the tumor microenvironment, including lactate dehydrogenase A (LDHA) upregulation. Therefore, the current study assessed the antitumor effect and the underlying mechanism of the LDHA inhibitor, sodium oxamate (Ox), combined with TACE, using the rabbit VX2 liver tumor model. VX2 liver tumor models were created in the left liver lobe of rabbits, and after 14 days of treatments, the rabbits were sacrificed for the collection of the tumor tissues and blood samples. The antitumor effects of Ox, and the combination of Ox and TACE, and changes in the tumor microenvironment after treatments were assessed by histopathological evaluation, and the safety of the treatments was analyzed by measuring changes in the serum levels of alanine aminotransferase, aspartate aminotransferase, blood urea nitrogen and creatinine. The results demonstrated that the combination of Ox and TACE notably improved antitumor effects compared with in the other groups, as it significantly inhibited tumor growth. Additionally, treatment with Ox + TACE downregulated vascular endothelial growth factor and matrix metalloproteinase-9, and enhanced the infiltration of CD3+ and CD8+ T cells into tumor tissues, thus suggesting that Ox + TACE may have a synergistic effect on increasing the infiltration of immune cells in the tumor microenvironment. With a well-tolerated and manageable impairment of hepatorenal function, targeting metabolic reprogramming could promote the efficacy of TACE, thus providing novel avenues for the future clinical management of patients with advanced HCC.

Recent clinical studies have shown that mutation of phosphatase and tensin homolog deleted on chromosome 10 (PTEN) gene in cancer cells may be associated with immunosuppressive tumor microenvironment (TME) and poor response to immune checkpoint blockade (ICB) therapy. Therefore, efficiently restoring PTEN gene expression in cancer cells is critical to improving the responding rate to ICB therapy. Here, we screened an adeno-associated virus (AAV) capsid for efficient PTEN gene delivery into B16F10 tumor cells. We demonstrated that intratumorally injected AAV6-PTEN successfully restored the tumor cell PTEN gene expression and effectively inhibited tumor progression by inducing tumor cell immunogenic cell death (ICD) and increasing immune cell infiltration. Moreover, we developed an anti-PD-1 loaded phospholipid-based phase separation gel (PPSG), which formed an in situ depot and sustainably release anti-PD-1 drugs within 42 days in vivo. In order to effectively inhibit the recurrence of melanoma, we further applied a triple therapy based on AAV6-PTEN, PPSG@anti-PD-1 and CpG, and showed that this triple therapy strategy enhanced the synergistic antitumor immune effect and also induced robust immune memory, which completely rejected tumor recurrence. We anticipate that this triple therapy could be used as a new tumor combination therapy with stronger immune activation capacity and tumor inhibition efficacy.

The immune functions of the body are intricately intertwined with the onset and advancement of tumors, and immunotherapy mediated by bioactive compounds has exhibited initial effectiveness in overcoming chemotherapy resistance and inhibiting tumor growth. However, the comprehensive interpretation of the roles played by immunologic components in the process of combating tumors remains to be elucidated. In this study, the Codonopsis pilosula glucofructan (CPG) prepared in our previous research was employed as an immunopotentiator, and the impacts of CPG on both the humoral and cellular immunity of S180 tumor-bearing mice were investigated. Results showed that CPG administration of 100 mg/kg could effectively inhibit tumor growth in mice with an inhibitory ratio of 45.37% and significantly improve the expression of Interleukin-2 (IL-2), Interferon-γ (IFN-γ), and Tumor Necrosis Factor-α (TNF-α). Additionally, CPG clearly enhanced B-cell-mediated humoral immunity and immune-cell-mediated cellular immunity, and, finally, induced S180 cell apoptosis by arresting cells in the G0/G1 phase, which might result from the IL-17 signaling pathway. These data may help to improve comprehension surrounding the roles of humoral and cellular immunity in anti-tumor immune responses.

UNASSIGNED: Intelligent hydrogels continue to encounter formidable obstacles in the field of cancer treatment. A wide variety of hydrogel materials have been designed for diverse purposes, but materials with satisfactory therapeutic effects are still urgently needed.
UNASSIGNED: Here, we prepared an injectable hydrogel by means of physical crosslinking. Carbon nanoparticle suspension injection (CNSI), a sentinel lymph node imaging agent that has been widely used in the clinic, with sodium β-glycerophosphate (β-GP) were added to a temperature-sensitive chitosan (CS) hydrogel (CS/GP@CN) as an agent for photothermal therapy (PTT). After evaluating the rheological, morphological, and structural properties of the hydrogel, we used 4T1 mouse breast cancer cells and B16 melanoma cells to assess its in vitro properties. Then, we intratumorally injected the hydrogel into BALB/c tumor-bearing mice to assess the in vivo PTT effect, antitumor immune response and the number of lung metastases.
UNASSIGNED: Surprisingly, this nanocarbon hydrogel called CS/GP@CN hydrogel not only had good biocompatibility and a great PTT effect under 808nm laser irradiation but also facilitated the maturation of dendritic cells to stimulate the antitumor immune response and had an extraordinary antimetastatic effect in the lungs.
UNASSIGNED: Overall, this innovative temperature-sensitive nanocarbon hydrogel, which exists in a liquid state at room temperature and transforms to a gel at 37 °C, is an outstanding local delivery platform with tremendous PTT potential and broad clinical application prospects.

Oncolytic viruses are able to lyse tumor cells selectively in the liver without killing normal hepatocytes, in addition to activating the immune response. Oncolytic virus therapy is expected to revolutionize the treatment of liver cancer, including hepatocellular carcinoma (HCC), one of the most frequent and fatal malignancies. In this study, reverse genetics techniques were exploited to load NA fragments of the A/PuertoRico/8/34 virus (PR8) with GV1001 peptides derived from human telomerase reverse transcriptase. An in vitro assessment of the therapeutic effect of the recombinant oncolytic virus was followed by an in vivo study in mice with HCC. The recombinant virus was verified by sequencing of the recombinant viral gene sequence, and viral virulence was detected by hemagglutination assays and based on the 50% tissue culture infectious dose (TCID50). The morphological structure of the virus was observed by electron microscopy, and GV1001 peptide was localized by cellular immunofluorescence. The selective cytotoxicity of the recombinant oncolytic virus in vitro was demonstrated in cultured HCC cells and normal hepatocytes, as only the tumor cells were killed; the normal cells were not significantly altered. Consistent with the in vitro results, the recombinant oncolytic influenza virus significantly inhibited liver tumor growth in mice in vivo, in addition to inducing an antitumor immune response, including an increase in the number of CD4+ and CD8+ T lymphocytes and, in turn, improving survival. Our results suggest that oncolytic influenza virus carrying GV1001 is a promising immunotherapy in patients with HCC.