YTHDF2 favors protumoral macrophage polarization and implies poor survival outcomes in triple negative breast cancer.

Patients with triple-negative breast cancer (TNBC) frequently experience resistance to chemotherapy, leading to recurrence. The approach of optimizing anti-tumoral immunological effect is promising in overcoming such resistance, given the heterogeneity and lack of biomarkers in TNBC. In this study, we focused on YTHDF2, an N6-methyladenosine (m6A) RNA-reader protein, in macrophages, one of the most abundant intra-tumoral immune cells. Using single-cell sequencing and ex vivo experiments, we discovered that YTHDF2 significantly promotes pro-tumoral phenotype polarization of macrophages and is closely associated with down-regulated antigen-presentation signaling to other immune cells in TNBC. The in vitro deprivation of YTHDF2 favors anti-tumoral effect. Expressions of multiple transcription factors, especially SPI1, were consistently observed in YTHDF2-high macrophages, providing potential therapeutic targets for new strategies. In conclusion, YTHDF2 in macrophages appears to promote pro-tumoral effects while suppressing immune activity, indicating the treatment targeting YTHDF2 or its transcription factors could be a promising strategy for chemoresistant TNBC.

Enhancing immune responses of ESC-based TAA cancer vaccines with a novel OMV delivery system.

Embryonic stem cell (ESC)-derived epitopes can act as therapeutic tumor vaccines against different types of tumors Jin (Adv Healthc Mater 2023). However, these epitopes have poor immunogenicity and stimulate insufficient CD8+ T cell responses, which motivated us to develop a new method to deliver and enhance their effectiveness. Bacterial outer membrane vesicles (OMVs) can serve as immunoadjuvants and act as a delivery vector for tumor antigens. In the current study, we engineered a new OMV platform for the co-delivery of ESC-derived tumor antigens and immune checkpoint inhibitors (PD-L1 antibody). An engineered Staphylococcal Protein A (SpA) was created to non-specifically bind to anti-PD-L1 antibody. SpyCatcher (SpC) and SpA were fused into the cell outer membrane protein OmpA to capture SpyTag-attached peptides and PD-L1 antibody, respectively. The modified OMV was able to efficiently conjugate with ESC-derived TAAs and PD-L1 antibody (SpC-OMVs + SpT-peptides + anti-PD-L1), increasing the residence time of TAAs in the body. The results showed that the combination therapy of ESC-based TAAs and PD-L1 antibody delivered by OMV had significant inhibitory effects in mouse tumor model. Specifically, it was effective in reducing tumor growth by enhancing IFN-γ-CD8+ T cell responses and increasing the number of CD8+ memory cells and antigen-specific T cells. Overall, the new OMV delivery system is a versatile platform that can enhance the immune responses of ESC-based TAA cancer vaccines.

Facile Synthesis of Novel Ti2C Nano Bipyramids for Photothermal and Photodynamic Therapy of Breast Cancer.

Photo-responsive synergetic therapeutics achieved significant attraction in cancer theranostic due to the versatile characteristics of nanomaterials. There have been substantial efforts in developing the simplest nano-design with exceptional synergistic properties and multifunctionalities. In this work, biocompatible Ti2C MXene nano bipyramids (MNBPs) were synthesized by hydrothermal method with dual functionalities of photothermal and photodynamic therapies. The MNBPs shape was obtained from two-dimensional (2D) Ti2C nanosheets by controlling the temperature of the reaction mixture. The structure of these Ti2C MNBPs was characterized by a high-resolution transmission electron microscope, scanning electron microscope, atomic force microscope, X-ray photoelectron spectroscopy, and X-ray diffraction. The Ti2C NBPs have shown exceptional photothermal properties with increased temperature to 72.3 °C under 808 nm laser irradiation. The designed nano bipyramids demonstrated excellent cellular uptake and biocompatibility. The Ti2C NBP has established a remarkable photothermal therapy (PTT) effect against 4T1 breast cancer cells. Moreover, Ti2C NBPs showed a profound response to UV light (6 mW/cm2) and produced reactive oxygen species, making them useful for photodynamic therapy (PDT). These in-vitro studies pave a new path to tune the properties of photo-responsive MXene nanosheets, indicating a potential use in biomedical applications.

Divergent trajectory of replication and intrinsic pathogenicity of SARS-CoV-2 Omicron post-BA.2/5 subvariants in the upper and lower respiratory tract.

BACKGROUND: Earlier Omicron subvariants including BA.1, BA.2, and BA.5 emerged in waves, with a subvariant replacing the previous one every few months. More recently, the post-BA.2/5 subvariants have acquired convergent substitutions in spike that facilitated their escape from humoral immunity and gained ACE2 binding capacity. However, the intrinsic pathogenicity and replication fitness of the evaluated post-BA.2/5 subvariants are not fully understood. METHODS: We systemically investigated the replication fitness and intrinsic pathogenicity of representative post-BA.2/5 subvariants (BL.1, BQ.1, BQ.1.1, XBB.1, CH.1.1, and XBB.1.5) in weanling (3-4 weeks), adult (8-10 weeks), and aged (10-12 months) mice. In addition, to better model Omicron replication in the human nasal epithelium, we further investigated the replication capacity of the post-BA.2/5 subvariants in human primary nasal epithelial cells. FINDINGS: We found that the evaluated post-BA.2/5 subvariants are consistently attenuated in mouse lungs but not in nasal turbinates when compared with their ancestral subvariants BA.2/5. Further investigations in primary human nasal epithelial cells revealed a gained replication fitness of XBB.1 and XBB.1.5 when compared to BA.2 and BA.5.2. INTERPRETATION: Our study revealed that the post-BA.2/5 subvariants are attenuated in lungs while increased in replication fitness in the nasal epithelium, indicating rapid adaptation of the circulating Omicron subvariants in the human populations. FUNDING: The full list of funding can be found at the Acknowledgements section.

Targeted IFNγ induction by a genetically engineered Salmonella typhimurium is the key to the liver metastasis inhibition in a mouse model of pancreatic neuroendocrine tumor.

Background: Liver metastasis is one of the primary causes of death for the patients with pancreatic neuroendocrine tumors (PNETs). However, no curative therapy has been developed so far. Methods: The anti-tumor efficacy of a genetically engineered tumor-targeting Salmonella typhimurium YB1 was evaluated on a non-functional INR1G9 liver metastasis model. Differential inflammatory factors were screened by Cytometric Bead Array. Antibody depletion assay and liver-targeted AAV2/8 expression vector were used for functional evaluation of the differential inflammatory factors. Results: We demonstrated that YB1 showed significant anti-tumor efficacy as a monotherapy. Since YB1 cannot infect INR1G9 cells, its anti-tumor effect was possibly due to the modulation of the tumor immune microenvironment. Two inflammatory factors IFNγ and CCL2 were elevated in the liver after YB1 administration, but only IFNγ was found to be responsible for the anti-tumor effect. Liver-targeted expression of IFNγ caused the activation of macrophages and NK cells, and reproduced the therapeutic effect of YB1 on liver metastasis. Conclusion: We demonstrated that YB1 may exhibit anti-tumor effect mainly based on IFNγ induction. Targeted IFNγ therapy can replace YB1 for treating liver metastasis of PNETs.

Discovery of potent and selective HPK1 inhibitors based on the 2,4-disubstituted pyrimidine scaffold with immune modulatory properties for ameliorating T cell exhaustion.

Hematopoietic progenitor kinase 1 (HPK1), a member of the mitogen-activated protein kinase (MAP4K) family, is a serine/threonine (SER/THR) kinase and has been demonstrated as a negative regulator of T cell receptor signaling. Targeting HPK1 has been considered as an attractive therapeutic strategy for immune-oncology. Here, we describe the discovery and structure-activity relationship (SAR) of potent HPK1 inhibitors based on the 2,4-disubstituted pyrimidine scaffold. Systematically SAR exploration afforded the desired compound HMC-H8 (F1) with potent HPK1 inhibition (IC50 = 1.11 nM) and highly selectivity profile. Compound HMC-H8 also exhibited robust inhibition of p-SLP 76 (IC50 = 283.0 nM) and promotion IL-2 release (EC50 = 157.08 nM), and INF-γ production in a dose-dependent manner in vitro assays. Strikingly, HMC-H8 shown effective immune reversal response in immunesuppressive condition. Moreover, Compound HMC-H8 displayed acceptable metabolic stability (T1/2 = 56.87 min), along with low CYP450 inhibition in human liver microsomes and good oral bioavailability (F = 15.05%) in rat. Furthermore, HMC-H8 was found to modulate the expression of c-Myc in Western blotting experiments. Taken together, this study provides new potent HPK1 inhibitors for further anticancer drug discovery based on immuno-oncology.

Bacterial outer-membrane vesicles promote Vγ9Vδ2 T cell oncolytic activity.

Background: Increasing evidence suggests the immune activation elicited by bacterial outer-membrane vesicles (OMVs) can initiate a potent anti-tumor immunity, facilitating the recognition and destruction of malignant cells. At present the pathways underlying this response remain poorly understood, though a role for innate-like cells such as γδ T cells has been suggested. Methods: Peripheral blood mononuclear cells (PBMCs) from healthy donors were co-cultured with E. coli MG1655 Δpal ΔlpxM OMVs and corresponding immune activation studied by cell marker expression and cytokine production. OMV-activated γδ T cells were co-cultured with cancer cell lines to determine cytotoxicity. Results: The vesicles induced a broad inflammatory response with γδ T cells observed as the predominant cell type to proliferate post-OMV challenge. Notably, the majority of γδ T cells were of the Vγ9Vδ2 type, known to respond to both bacterial metabolites and stress markers present on tumor cells. We observed robust cytolytic activity of Vγ9Vδ2 T cells against both breast and leukaemia cell lines (SkBr3 and Nalm6 respectively) after OMV-mediated expansion. Conclusions: Our findings identify for the first time, that OMV-challenge stimulates the expansion of Vγ9Vδ2 T cells which subsequently present anti-tumor capabilities. We propose that OMV-mediated immune activation leverages the anti-microbial/anti-tumor capacity of Vγ9Vδ2 T cells, an axis amenable for improved future therapeutics.

Engineered Salmonella inhibits GPX4 expression and induces ferroptosis to suppress glioma growth in vitro and in vivo.

PURPOSE: Glioma is a life-threatening malignancy where conventional therapies are ineffective. Bacterial cancer therapy has shown potential for glioma treatment, in particular, the facultative anaerobe Salmonella has been extensively studied. Meanwhile, ferroptosis is a newly characterized form of cell death. Nevertheless, the role of ferroptosis in Salmonella-induced tumour cell death remains unclear. Therefore, we aim to elucidate whether Salmonella YB1 exerts therapeutic effects via inducing ferroptosis in glioma. METHODS: Following Salmonella YB1 infection, mRNA sequencing was applied to detect ferroptosis-related gene expression and the levels of reactive oxygen species, malondialdehyde, and glutathione were quantified. Transmission electron microscopy (TEM) was then used to observe the changes in the mitochondrial morphology of glioma cells. The role of ferroptosis in the anti-tumor effect of YB1 was assessed in vivo in mouse tumor xenograft models. RESULTS: Whole-transcriptome analysis revealed that Salmonella YB1 infection alters ferroptosis-related gene expression in the U87 glioma cell line. Moreover, we found that Salmonella-induced ferroptosis is correlated with reduced levels of glutathione and glutathione peroxidase-4 (GPX4) and increased levels of reactive oxygen species and malondialdehyde in vitro. Meanwhile, TEM revealed that mitochondria are shrunken and mitochondrial membrane density increases in infected glioma cells. Experiments in vivo further showed that tumor growth in the Salmonella-treated group was significantly slower compared to the control and Fer-1 groups. However, Salmonella-induced tumor suppression can be reversed in vivo by Fer-1 treatment. CONCLUSION: Salmonella YB1 inhibits GPX4 expression and induces ferroptosis to suppress glioma growth. Hence, ferroptosis regulation might represent a promising strategy to improve the efficacy of bacterial cancer therapy.

A Bayesian approach to estimate MHC-peptide binding threshold.

Major histocompatibility complex (MHC)-peptide binding is a critical step in enabling a peptide to serve as an antigen for T-cell recognition. Accurate prediction of this binding can facilitate various applications in immunotherapy. While many existing methods offer good predictive power for the binding affinity of a peptide to a specific MHC, few models attempt to infer the binding threshold that distinguishes binding sequences. These models often rely on experience-based ad hoc criteria, such as 500 or 1000nM. However, different MHCs may have different binding thresholds. As such, there is a need for an automatic, data-driven method to determine an accurate binding threshold. In this study, we proposed a Bayesian model that jointly infers core locations (binding sites), the binding affinity and the binding threshold. Our model provided the posterior distribution of the binding threshold, enabling accurate determination of an appropriate threshold for each MHC. To evaluate the performance of our method under different scenarios, we conducted simulation studies with varying dominant levels of motif distributions and proportions of random sequences. These simulation studies showed desirable estimation accuracy and robustness of our model. Additionally, when applied to real data, our results outperformed commonly used thresholds.

A Sulfur-Bridging Sulfonate-Modified Zinc(II) Phthalocyanine Nanoliposome Possessing Hybrid Type I and Type II Photoreactions with Efficient Photodynamic Anticancer Effects.

Phthalocyanines are potentially promising photosensitizers (PSs) for photodynamic therapy (PDT), but the inherent defects such as aggregation-caused quenching effects and non-specific toxicity severely hinder their further application in PDT. Herein, we synthesized two zinc(II) phthalocyanines (PcSA and PcOA) monosubstituted with a sulphonate group in the alpha position with "O bridge" and "S bridge" as bonds and prepared a liposomal nanophotosensitizer (PcSA@Lip) by thin-film hydration method to regulate the aggregation of PcSA in the aqueous solution and enhance its tumor targeting ability. PcSA@Lip exhibited highly efficient production of superoxide radical (O2∙-) and singlet oxygen (1O2) in water under light irradiation, which were 2.6-fold and 15.4-fold higher than those of free PcSA, respectively. Furthermore, PcSA@Lip was able to accumulate selectively in tumors after intravenous injection with the fluorescence intensity ratio of tumors to livers was 4.1:1. The significant tumor inhibition effects resulted in a 98% tumor inhibition rate after PcSA@Lip was injected intravenously at an ultra-low PcSA@Lip dose (0.8 nmol g-1 PcSA) and light dose (30 J cm-2). Therefore, the liposomal PcSA@Lip is a prospective nanophotosensitizer possessing hybrid type I and type II photoreactions with efficient photodynamic anticancer effects.

The Lung Microbiome: A New Frontier for Lung and Brain Disease.

Due to the limitations of culture techniques, the lung in a healthy state is traditionally considered to be a sterile organ. With the development of non-culture-dependent techniques, the presence of low-biomass microbiomes in the lungs has been identified. The species of the lung microbiome are similar to those of the oral microbiome, suggesting that the microbiome is derived passively within the lungs from the oral cavity via micro-aspiration. Elimination, immigration, and relative growth within its communities all contribute to the composition of the lung microbiome. The lung microbiome is reportedly altered in many lung diseases that have not traditionally been considered infectious or microbial, and potential pathways of microbe-host crosstalk are emerging. Recent studies have shown that the lung microbiome also plays an important role in brain autoimmunity. There is a close relationship between the lungs and the brain, which can be called the lung-brain axis. However, the problem now is that it is not well understood how the lung microbiota plays a role in the disease-specifically, whether there is a causal connection between disease and the lung microbiome. The lung microbiome includes bacteria, archaea, fungi, protozoa, and viruses. However, fungi and viruses have not been fully studied compared to bacteria in the lungs. In this review, we mainly discuss the role of the lung microbiome in chronic lung diseases and, in particular, we summarize the recent progress of the lung microbiome in multiple sclerosis, as well as the lung-brain axis.

The Epitope Basis of Embryonic Stem Cell-Induced Antitumor Immunity against Bladder Cancer.

Embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) share many cellular and molecular features with cancer cells. Taking advantage of these similarities, stem cells are effective vaccines against cancers in animal models. However, the molecular basis is not well understood, which hinders the development of effective cancer vaccines. Here, prophylactic and therapeutic bladder cancer vaccines composed of allogeneic ESCs and CpG with or without granulocyte macrophage colony stimulating factor are tested. The ESC-based cancer vaccines are able to induce specific antitumor immunity including stimulating cytotoxic CD8+ T cells and memory CD4+ T cells, reducing myeloid-derived suppressor cells, and preventing bladder cancer growth in mouse models. Furthermore, several genes that are overexpressed in both ESCs and tumors are identified. An epitope-based vaccine designed with shared overexpressed proteins induces specific antitumor immunity and reduces bladder cancer growth. Functional epitopes underlying the action of stem cell-based vaccines against bladder cancer are identified and it is confirmed that ESC-based anticancer vaccines have great potential. A systematic approach is provided here to developing novel effective epitope-based cancer vaccines in the future.

Thermosensitive Liposomal Nanoplatform Based on Metal-Free Phthalocyanine with Copper(II)-Regulated Photoactivities.

This work reports the development of a multifunctional thermosensitive liposomal nanoplatform (PcS4 @Lip-FA) based on a metal-free phthalocyanine modified with tetra-sulfonates (PcPS4 ), which exhibited photodynamic and photothermal activities simultaneously. Upon irradiation with a near infrared laser, thermosensitive PcS4 @Lip-FA could release PcS4 as a result of the local hyperthermia of PcS4 . Interestingly, PcS4 could easily chelate with Cu2+ , leading to the enhancement of photothermal activity and decrease of photodynamic activity. In addition, in vivo fluorescence imaging revealed that PcS4 @Lip-FA could selectively accumulate in tumor tissue of H22 tumor-bearing mice after tail vein injection, and exhibited a significant anticancer phototherapeutic effect, with a tumor inhibition rate of 83.5 %. Therefore, PcPS4 @Lip-FA has realized fluorescence imaging-guided combined cancer treatment, providing a promising multifunctional nanoplatform for cancer diagnostics and therapy.

Glu-Urea-Lys Scaffold Functionalized Superparamagnetic Iron Oxide Nanoparticles Targeting PSMA for In Vivo Molecular MRI of Prostate Cancer.

The prostate specific membrane antigen (PSMA), extensively overexpressed on prostate cancer (PCa) cell surface, has been validated as a diagnostic biomarker for PCa. However, insufficient attention has been paid to the development of PSMA-specific probes loaded with small chemical molecules for the in vivo molecular imaging of PCa. In this study, we innovatively labelled superparamagnetic iron oxide nanoparticles with a PSMA-targeting Glu-Urea-Lys scaffold. An optimized synthetic route was developed to offer a physiochemically stable probe. The probe demonstrated high binding affinity (0.38 ± 0.08 µg(Fe)/mL) and binding specificity to PSMA expressed on prostate cancer cell surface in vitro. In a xenograft PCa mouse model, significant negative contrast of the implanted prostate cancer xenograft could be specifically observed by MRI 6 h after tail vein injection of the tracer (Fe, 20 mg/kg), exhibiting its potential to exclusively enhance magnetic resonance detection of PCa.

Molecular and Supramolecular Approach to Highly Photocytotoxic Phthalocyanines with Dual Cell Uptake Pathways and Albumin-Enhanced Tumor Targeting.

Phototherapy for non-invasive cancer treatment has been extensively studied. An urgent challenge in phototherapy application is to fabricate appropriate targeted agents to achieve efficient therapeutic effect. Herein, a molecular and supramolecular approach for targeting phototherapy was reasonably designed and realized through the axial sulfonate modification of silicon(IV) phthalocyanines (Pcs), followed by supramolecular interaction with albumin. This approach can not only improve the photoactivities (e.g., fluorescence emission and reactive oxygen species production) of the Pcs but also enhance their tumor targeting. Most importantly, one of the deigned Pcs (4) can target HepG2 cells through dual cell pathways, leading to an extremely high phototoxicity with an EC50 (i.e., concentration of Pcs to kill 50% of cells under light irradiation) value of 2.0 nM. This finding presents a feasible strategy to realize efficient targeting phototherapy.

Isosteviol Sodium Ameliorates Dextran Sodium Sulfate-Induced Chronic Colitis through the Regulation of Metabolic Profiling, Macrophage Polarization, and NF-κB Pathway.

Inflammatory bowel diseases (IBDs) constitute a group of chronic intestinal conditions prominently featuring deranged metabolism. Effective pharmacological treatments for IBDs are lacking. Isosteviol sodium (STV-Na) exhibits anti-inflammatory activity and may offer therapeutic benefits in chronic colitis. However, the associated mechanism remains unclear. This study is aimed at exploring the therapeutic effects of STV-Na against chronic colitis in terms of metabolic reprogramming and macrophage polarization. Results show that STV-Na attenuated weight loss and colonic pathological damage and restored the hematological and biochemical parameters in chronic colitis mice models. STV-Na also restored intestinal permeability by increasing the goblet cell numbers, which was accompanied by lowered plasma lipopolysaccharide and diamine oxidase levels. Metabolomic analysis highlighted 102 candidate biomarkers and 5 vital pathways that may be crucial in the potential pharmacological mechanism of STV-Na in regulating intestinal inflammation and oxidative stress. These pathways were glycerophospholipid metabolism, phenylalanine metabolism, phenylalanine, tyrosine and tryptophan biosynthesis, the pentose phosphate pathway, and phosphonate and phosphinate metabolism. Furthermore, STV-Na significantly decreased M1 macrophage polarization in the spleen and colon. The mRNA and protein levels of IL-1ß, TNF-α, and NF-κB/p65 in colonic tissue from the colitis mice were decreased after the STV-Na treatment. Overall, STV-Na could alleviate chronic colitis by suppressing oxidative stress and inflammation levels, reprogramming the metabolic profile, inhibiting macrophage polarization, and suppressing the NF-κB/p65 signaling pathway. STV-Na remains a promising candidate drug for treating IBDs.

Current status of intratumour microbiome in cancer and engineered exogenous microbiota as a promising therapeutic strategy.

Research on the relationship between microbiome and cancer has made significant progress in the past few decades. It is now known that the gut microbiome has multiple effects on tumour biology. However, the relationship between intratumoral bacteria and cancers remains unclear. Growing evidence suggests that intratumoral bacteria are important components of the microenvironment in several types of cancers. Furthermore, several studies have demonstrated that intratumoral bacteria may directly influence tumorigenesis, progression and responses to treatment. Limited studies have been conducted on intratumoral bacteria, and using intratumoral bacteria to treat tumours remains a challenge. Bacteria have been studied as anticancer therapeutics since the 19th century when William B. Coley successfully treated patients with inoperable sarcomas using Streptococcus pyogenes. With the development of synthetic biological approaches, several bacterial species have been genetically engineered to increase their applicability for cancer treatment. Genetically engineered bacteria for cancer therapy have unique properties compared to other treatment methods. They can specifically accumulate within tumours and inhibit cancer growth. In addition, genetically engineered bacteria may be used as a vector to deliver antitumour agents or combined with radiation and chemotherapy to synergise the effectiveness of cancer treatment. However, various problems in treating tumours with genetically engineered bacteria need to be addressed. In this review, we focus on the role of intratumoral bacteria on tumour initiation, progression and responses to chemotherapy or immunotherapy. Moreover, we summarised the recent progress in the treatment of tumours with genetically engineered bacteria.

Aggregation-Enhanced Sonodynamic Activity of Phthalocyanine-Artesunate Conjugates.

The clinical prospect of sonodynamic therapy (SDT) has not been fully realized due to the scarcity of efficient sonosensitizers. Herein, we designed phthalocyanine-artesunate conjugates (e.g. ZnPcT4 A), which could generate up to ca. 10-fold more reactive oxygen species (ROS) than the known sonosensitizer protoporphyrin IX. Meanwhile, an interesting and significant finding of aggregation-enhanced sonodynamic activity (AESA) was observed for the first time. ZnPcT4 A showed about 60-fold higher sonodynamic ROS generation in the aggregated form than in the disaggregated form in aqueous solutions. That could be attributed to the boosted ultrasonic cavitation of nanostructures. The level of the AESA effect depended on the aggregation ability of sonosensitizer molecules and the particle size of their aggregates. Moreover, biological studies demonstrated that ZnPcT4 A had high anticancer activities and biosafety. This study thus opens up a new avenue the development of efficient organic sonosensitizers.

Near-Infrared Responsive Membrane Nanovesicles Amplify Homologous Targeting Delivery of Anti-PD Immunotherapy against Metastatic Tumors.

The major obstacles of anti-PD therapy in metastatic tumors are limited drug delivery in primary tumors and metastatic foci, and the lack of tumor-infiltrating lymphocytes (TILs). Here, the authors constructed a novel cellular membrane nanovesicles platform (M/IR NPs) based on homologous targeting and near-infrared (NIR) responsive release strategy to potentiate PD-1/PD-L1 blockade therapy against metastatic tumors. In tumor-bearing mice, biomimetic M/IR NPs targeted both primary tumors and their lung metastases. Upon laser irradiation, M/IR NPs reduced cancer-associated fibroblasts (CAFs) in tumor microenvironment, thus increasing the penetration of TILs. When shed from homologous tumor cell membranes, positively charged nanoparticles (IR NPs) core can capture released tumor-associated antigens, thereby enhancing the antigen-presenting ability of DCs to activate cytotoxic T lymphocytes. When the photothermal conversion temperature under NIR-laser is higher than 42 °C, M/IR NPs initiated the rupture of cell membranes and the responsive release of PD-1/PD-L1 inhibitor BMS, which significantly attenuated tumor-associated immunosuppression and synergistically induced T cellular immunity to inhibit the tumor growth and metastasis. Overall, biomimetic M/IR NPs can improve the targeting and therapeutic efficacy of anti-PD therapy in primary tumors and metastases, opening up a new avenue for the diagnosis and treatment of metastatic tumors in the future.

Thermal-sensitive lipid nanoparticles potentiate anti-PD therapy through enhancing drug penetration and T lymphocytes infiltration in metastatic tumor.

The response rate of anti-PD therapy in most cancer patients remains low. Therapeutic drug and tumor-infiltrating lymphocytes (TILs) are usually obstructed by the stromal region within tumor microenvironment (TME) rather than distributed around tumor cells, thus unable to induce the immune response of cytotoxic T cells. Here, we constructed the cationic thermosensitive lipid nanoparticles IR780/DPPC/BMS by introducing cationic NIR photosensitizer IR-780 iodide (IR780) modified lipid components, thermosensitive lipid DPPC and PD-1/PD-L1 inhibitor BMS202 (BMS). Upon laser irradiation, IR780/DPPC/BMS penetrated into deep tumor, and reduced cancer-associated fibroblasts (CAFs) around tumor cells to remodel the spatial distribution of TILs in TME. Interestingly, the cationic IR780/DPPC/BMS could capture released tumor-associated antigens (TAAs), thereby enhancing the antigen-presenting ability of DCs to activate cytotoxic T lymphocytes. Moreover, IR780/DPPC/BMS initiated gel-liquid crystal phase transition under laser irradiation, accelerating the disintegration of lipid bilayer structure and leading to the responsive release of BMS, which would reverse the tumor immunosuppression state by blocking PD-1/PD-L1 pathway for a long term. This combination treatment can synergistically exert the antitumor immune response and inhibit the tumor growth and metastasis.