HMMR triggers immune evasion of hepatocellular carcinoma by inactivation of phagocyte killing.

Hepatocellular carcinoma (HCC) acquires an immunosuppressive microenvironment, leading to unbeneficial therapeutic outcomes. Hyaluronan-mediated motility receptor (HMMR) plays a crucial role in tumor progression. Here, we found that aberrant expression of HMMR could be a predictive biomarker for the immune suppressive microenvironment of HCC, but the mechanism remains unclear. We established an HMMR-/- liver cancer mouse model to elucidate the HMMR-mediated mechanism of the dysregulated "don't eat me" signal. HMMR knockout inhibited liver cancer growth and induced phagocytosis. HMMRhigh liver cancer cells escaped from phagocytosis via sustaining CD47 signaling. Patients with HMMRhighCD47high expression showed a worse prognosis than those with HMMRlowCD47low expression. HMMR formed a complex with FAK/SRC in the cytoplasm to activate NF-κB signaling, which could be independent of membrane interaction with CD44. Notably, targeting HMMR could enhance anti-PD-1 treatment efficiency by recruiting CD8+ T cells. Overall, our data revealed a regulatory mechanism of the "don't eat me" signal and knockdown of HMMR for enhancing anti-PD-1 treatment.

Intratumoral Microbiota Composition Regulates Chemoimmunotherapy Response in Esophageal Squamous Cell Carcinoma.

Neoadjuvant chemoimmunotherapy (NACI) has shown promise in the treatment of resectable esophageal squamous cell carcinoma (ESCC). The microbiomes of patients can impact therapy response, and previous studies have demonstrated that intestinal microbiota influences cancer immunotherapy by activating gut immunity. Here, we investigated the effects of intratumoral microbiota on the response of patients with ESCC to NACI. Intratumoral microbiota signatures of ß-diversity were disparate and predicted the treatment efficiency of NACI. The enrichment of Streptococcus positively correlated with GrzB+ and CD8+ T-cell infiltration in tumor tissues. The abundance of Streptococcus could predict prolonged disease-free survival in ESCC. Single-cell RNA sequencing demonstrated that responders displayed a higher proportion of CD8+ effector memory T cells but a lower proportion of CD4+ regulatory T cells. Mice that underwent fecal microbial transplantation or intestinal colonization with Streptococcus from responders showed enrichment of Streptococcus in tumor tissues, elevated tumor-infiltrating CD8+ T cells, and a favorable response to anti-PD-1 treatment. Collectively, this study suggests that intratumoral Streptococcus signatures could predict NACI response and sheds light on the potential clinical utility of intratumoral microbiota for cancer immunotherapy. SIGNIFICANCE: Analysis of intratumoral microbiota in patients with esophageal cancer identifies a microbiota signature that is associated with chemoimmunotherapy response and reveals that Streptococcus induces a favorable response by stimulating CD8+ T-cell infiltration. See related commentary by Sfanos, p. 2985.

Mitochondria-targeting polydopamine-coated nanodrugs for effective photothermal- and chemo-synergistic therapies against lung cancer.

Targeting mitochondria via nano platform emerged as an attractive anti-tumor pathway due to the central regulation role in cellar apoptosis and drug resistance. Here, a mitochondria-targeting nanoparticle (TOS-PDA-PEG-TPP) was designed to precisely deliver polydopamine (PDA) as the photothermal agent and alpha-tocopherol succinate (α-TOS) as the chemotherapeutic drug to the mitochondria of the tumor cells, which inhibits the tumor growth through chemo- and photothermal- synergistic therapies. TOS-PDA-PEG-TPP was constructed by coating PDA on the surface of TOS NPs self-assembled by α-TOS, followed by grafting PEG and triphenylphosphonium (TPP) on their surface to prolong the blood circulation time and target delivery of TOS and PDA to the mitochondria of tumor cells. In vitro studies showed that TOS-PDA-PEG-TPP could be efficiently internalized by tumor cells and accumulated at mitochondria, resulting in cellular apoptosis and synergistic inhibition of tumor cell proliferation. In vivo studies demonstrated that TOS-PDA-PEG-TPP could be efficiently localized at tumor sites and significantly restrain the tumor growth under NIR irradiation without apparent toxicity or deleterious effects. Conclusively, the combination strategy adopted for functional nanodrugs construction aimed at target-delivering therapeutic agents with different action mechanisms to the same intracellular organelles can be extended to other nanodrugs-dependent therapeutic systems.

Colorimetric and Fluorescent Dual-Modality Sensing Platform Based on Fluorescent Nanozyme.

Compared with natural enzymes, nanozymes based on carbonaceous nanomaterials are advantages due to high stability, good biocompatibility, and the possibility of multifunctionalities through materials engineering at an atomic level. Herein, we present a sensing platform using a nitrogen-doped graphene quantum dot (NGQD) as a highly efficient fluorescent peroxidase mimic, which enables a colorimetric/fluorescent dual-modality platform for detection of hydrogen peroxide (H2O2) and biomolecules (ascorbic acid-AA, acid phosphatase-ACP) with high sensitivity. NGQD is synthesized using a simple hydrothermal process, which has advantages of high production yield and potential for large-scale preparation. NGQD with uniform size (3.0 ± 0.6 nm) and a single-layer graphene structure exhibits bright and stable fluorescence. N-doping and ultrasmall size endow NGQD with high peroxidase-mimicking activity with an obviously reduced Michaelis-Menten constant (K m) in comparison with natural horseradish peroxidase. Taking advantages of both high nanozyme activity and unique fluorescence property of NGQD, a colorimetric and fluorescent dual-modality platform capable of detecting H2O2 and biomolecules (AA, ACP) with high sensitivity is developed as the proof-of-concept demonstration. Furthermore, the mechanisms underlying the nanozyme activity and biosensing are investigated.