Enhance Tumor Immunogenicity Research Articles

Pyrithione zinc alters mismatch repair to trigger tumor immunogenicity.

Mismatch repair deficiency (dMMR) cancers are highly sensitive to immunotherapy, but only account for a small fraction of cancer patients. How to increase immunotherapy efficacy on MMR-proficient (pMMR) cancer is still a major challenge. This study demonstrates that pyrithione zinc (PYZ), an FDA-approved drug, can enhance tumor immunogenicity via altering MMR and activating STING signaling. Mechanistically, PYZ elevates levels of ROS, leading to the upregulation of HIF-1α and DNA damage, while also inhibiting the expression of DNA mismatch repair proteins MSH2 and MSH6, together promoting DNA damage accumulation. Therefore, the administration of PYZ results in the accumulation of DNA damage, leading to the activation of STING signaling, which enhances tumor immunogenicity. Knockout of Sting diminishes the activation of IFN-I signaling induced by PYZ and reduces tumor immunogenicity. Furthermore, in vivo administration of PYZ promotes the infiltration of CD8+ T cells into the tumor and inhibits tumor growth, an effect that is attenuated in Nude mice or mice with CD8+ T cell depletion or deficiency of Ifnar. Overall, our findings showed that pyrithione zinc could trigger tumor immunogenicity by downregulating MMR machinery and activating STING pathway in tumor cells, and provide a translational approach to improve immunotherapy on pMMR cancer.

The feasibility of combining immune checkpoint inhibitors with cancer-related fibroblasts for the treatment of tumors

In tumor therapy, immune checkpoint inhibitors (ICIs) are widely utilized. However, in most cases, patients with colorectal cancer and breast cancer have a low response rate to ICIs monotherapy. By directly or indirectly inhibiting T cells, Cancer-associated fibroblasts (CAFs) impact the immune response against tumors and immune cells' sensitivity to immune checkpoints. At present, the research on targeted CAFs for tumor treatment has become a hot topic. This paper analyzed the mechanism of immune resistance to ICIs in some tumor patients, found that CAFs promoted the formation of immune resistance in patients, and analyzed two ways of targeting CAFs to inhibit tumor progression and found that the drug GKT137831 could restore the sensitivity of patients to ICIs by inhibiting CAFs. The combined treatment of ICIs and CAFs provides a reference for the clinical treatment of tumors. However, CAFs are a highly heterogeneous cell population, so it is necessary to find more precise CAFs targeting drugs to enhance tumor immunogenicity and improve tumor sensitivity to ICIs through combination therapy.

Nanomedicine based on chemotherapy-induced immunogenic death combined with immunotherapy to enhance antitumor immunity.

Chemo-immunotherapy based on inducing tumor immunogenic cell death (ICD)with chemotherapy drugs has filled the gaps between traditional chemotherapy and immunotherapy. It is verified that paclitaxel (PTX) can induce breast tumor ICD. From this basis, a kind of nanoparticle that can efficiently deliver different drug components simultaneously is constructed. The purpose of this study is for the sake of exploring the scheme of chemotherapy-induced ICD combined with other immunotherapy to enhance tumor immunogenicity and inhibit the growth, metastasis, and recurrence of breast tumors, so as to provide a research basis for solving the tough problem of breast cancer treatment. Nanomedicine loaded with PTX, small interference RNA that suppresses CD47 expression (CD47siRNA, siCD47), and immunomodulator R848 were prepared by the double emulsification method. The hydrodynamic diameter and zeta potential of NP/PTX/siCD47/R848 were characterized. Established the tumor-bearing mice model of mouse breast cancer cell line (4T1) in situ and observed the effect of intravenous injection of NP/PTX/siCD47/R848 on the growth of 4T1 tumor in situ. Flow cytometry was used to detect the effect of drugs on tumor immune cells. NP/PTX/siCD47/R848 nano-drug with tumor therapeutic potential were successfully prepared by double emulsification method, with particle size of 121.5 ± 4.5nm and surface potential of 36.1 ± 2.5mV. The calreticulin on the surface of cell membrane and extracellular ATP or HMGB1 of 4T1 cells increased through treatment with NPs. NP/PTX-treated tumor cells could cause activation of BMDCs and BMDMs. After intravenous injection, NP/PTX could quickly reach the tumor site and accumulate for 24h. The weight and volume of tumor in situ in the breast cancer model mice injected with nanomedicine through the tail vein were significantly lower than those in the PBS group. The ratio of CD8+/CD4+ T cells in the tumor microenvironment and the percentage of dendritic cells in peripheral blood increased significantly in breast cancer model mice injected with nano-drugs through the tail vein. Briefly, the chemotherapeutic drug paclitaxel can induce breast cancer to induce ICD. The nanomedicine which can deliver PTX, CD47siRNA, and R848 at the same time was prepared by double emulsification. NP/PTX/siCD47/R848 nano-drug can be enriched in the tumor site. The experiment of 4T1 cell tumor-bearing mice shows that the nano-drug can enhance tumor immunogenicity and inhibit breast tumor growth, which provides a new scheme for breast cancer treatment. (Graphical abstract).

LNS8801: An enantiomerically pure agonist of the G protein-coupled estrogen receptor suitable for clinical development.

Estrogen effects in tissue are mediated in part through activation of the surface estrogen receptor GPER, a broadly expressed G protein-coupled receptor that impacts a wide range of normal and pathologic processes, including metabolism, vascular health, inflammation, and cancer. A commonly used synthetic and specific GPER agonist, named G-1, antagonizes tumors by promoting cellular differentiation and enhancing tumor immunogenicity. G-1 is a racemic compound, and since its discovery, the question of whether both enantiomers display agonist activity or the agonist activity resides primarily in a single enantiomer has never been fully resolved. Herein, we disclose the isolation of the pure enantiomers of G-1 and determine that the desirable activity resides exclusively in 1 enantiomer, named LNS8801, whose configuration we have unambiguously determined by single crystal x-ray structure analysis. Using preclinical models, we show that LNS8801 suppresses cancer in a GPER-dependent manner and that LNS8801 is efficacious when administered orally. Further, we show that GPER is widely, but not ubiquitously, expressed in both normal and malignant human tissues. In addition, an attenuated response to LNS8801 is observed in a common germline coding variant in human GPER. These findings support ongoing human cancer trials with LNS8801 and suggest that the germline GPER genotype may serve as a predictive biomarker of therapeutic response.

A Highly Potent Os@Au‐TPA Coordination Structure‐Based Sonosensitizer for Tumor Sono‐Immunotherapies

AbstractUltrasound (US) becomes an appealing modality for stimulating or amplifying immune responses during cancer therapy, which is also termed sono‐immunotherapy. However, the clinical prospect has not been fully realized due to the scarcity of efficient sonosensitizers. Herein, for the first time a novel Os‐doped Au‐tri(pyridin‐4‐yl) amine coordination structure (Os@Au‐TPA)‐based sonosensitizer is originally designed and synthesized for sono‐immunotherapy of breast‐metastasized tumors. Impressively, Os@Au‐TPA shows much higher US‐mediated 1O2‐producing activity than Au‐TPA as well as the other traditional sonosensitizers, for example, ≈41.6 folds to ce6, 19.5 times to Protoporphyrin IX (PpIX), 12.0 to Indocyanine Green (ICG), and 11.1 to Iron phthalocyanine (Pc(Fe)). The Os@Au‐TPA can not only generate abundant ROS upon US irradiation to implement sonodynamic therapy (SDT), stimulating cell apoptosis and further immunogenic cell death, but can also generate O2 to alleviate hypoxia to promote the polarization of M2 to M1 macrophages to enhance tumor immunogenicity. As a result, when combined with PD‐L1 antibody, it remodels the immunosuppressive tumor microenvironment, achieves concurrent sonodynamic‐triggered immune activation, and eradicates both the original and distant‐metastasized tumors efficiently. This work not only provides a new strategy to construct potent sonosensitizers from pyridine‐metal coordination structures but also proves that sonosensitizers with high performance are crucial in boosting cancer sono‐immunotherapy.

Engineered Biomimetic Cancer Cell Membrane Nanosystems Trigger Gas-Immunometabolic Therapy for Spinal-Metastasized Tumors.

Despite great progress in enhancing tumor immunogenicity, conventional gas therapy cannot effectively reverse the tumor immunosuppressive microenvironment (TIME), limiting immunotherapy. The development of therapeutic gases that are tumor microenvironment responsive and efficiently reverse the TIME for precisely targeted tumor gas-immunometabolic therapy remains a great challenge. In this study, a novel cancer cell membrane-encapsulated pH-responsive nitric oxide (NO)-releasing biomimetic nanosystem (MP@AL) is prepared. Lactate oxidase (Lox) in MP@AL consumed oxygen to promote the decomposition of lactate, a metabolic by-product of tumor glycolysis, and the generation of H2O2, while L-arginine (L-Arg) in MP@AL is oxidized by H2O2 to generate nitric oxide (NO). For one thing, NO led to mitochondrial dysfunction in tumor cells to reduce oxygen consumption and promote the efficiency of Lox in lactate decomposition, thus reversing lactate-induced TIME; for another, NO effectively triggered immunogenic cell death, activated anti-tumor immune response and long-term immune memory, and ensured a favorable effect in the synergistic interaction with PD-L1 antibody for inhibiting tumor growth and recurrence. Therefore, a novel gas-immunometabolic therapy dual closed-loop nanosystem for enhancing tumor immunogenicity and remodeling lactate-induced TIME is established. Overall, this work will provide new ideas for gas therapy to effectively remodel the TIME to enhance cancer immunotherapy.

“Balloon-like” biomimetic erythrocyte vesicles potentiate photodynamic therapy for inducing immunogenic cell death

Photodynamic therapy (PDT) for cancer is known for its minimal invasiveness and safe characteristics, but the hypoxic tumor microenvironment still limits efficacy. Herein, we have developed a novel “balloon-like” biomimetic erythrocyte vesicle, which is constructed by loading chlorin e6 (Ce6) and oxygenated hemoglobin (Hb) in a folate (FA)-modified, PEGylated liposome, denoted as Ce6-Hb-FA@lip (CHFL). The CHFL exhibits high biocompatibility and good stability in PBS solution. Moreover, CHFL possesses the “balloon-like” elastic structure for oxygen binding with the change of volume. Both in vitro and in vivo studies demonstrate an effective PDT of CHFL, which significantly reverses the hypoxic microenvironment of tumor cells through the targeted cotransmission of Ce6 and Hb. Additionally, this biomimetic erythrocyte vesicle can induce oxidative stress to enhance tumor immunogenicity and trigger immunogenic cell death (ICD). Thus, the dying tumor cells can activate both dendritic cells (DCs) and T lymphocytes, which, in turn, initiates the antitumor immune response by releasing the damage-associated molecular patterns (DAMPs). This effective and safe platform holds great promise in the development of nanomedicines for innovative oxygen-enhanced PDT in the treatment of cancer.

Assembly of 2′,3′-Cyclic guanosine Monophosphate-Adenosine monophosphate and their spontaneous intracellular disassembly for enhanced antitumor immunity via natural STING pathway activation

The stimulator of interferon genes (STING) pathway plays an important role in remodeling the immunosuppressive tumor microenvironment (TME). Cyclic dinucleotides (CDNs), the natural ligands of STING, activate innate immunity to enhance tumor immunogenicity. However, the anionic properties of CDNs result in poor membrane permeability, while their rapid metabolism by enzymes hinders the efficient targeting and activation of STING in vitro and in vivo. To improve the bioavailability and antitumor immunity of CDNs, we designed a hydrogen-bonding-based supramolecular approach for 2′,3′-cyclic guanosine monophosphate (GMP)-adenosine monophosphate (AMP) (cGAMP). Leveraging the synthetic molecules cytosine-uracil-hexane (CUH), we formulated supramolecular micelles of cGAMP via specific hydrogen bonds in aqueous solutions. Micelles comprising the CUH-cGAMP complex enhanced the biological efficacy of cGAMP by increasing its stability, thereby prolonging the activation of STING-mediated innate and adaptive immunity. We demonstrated that CUH-cGAMP stands as a promising candidate for immunotherapy, exhibiting significant inhibition of tumor growth in a CT26 syngeneic mouse model.

Priming of cancer-immunity cycle by alleviating hypoxia-induced ferroptosis resistance and immunosuppression

Stimulating a robust cancer-immunity cycle (CIC) holds promising potential for eliciting potent and enduring immune responses for cancer immunotherapy. However, designing a therapeutic nanomaterial capable of both enhancing tumor immunogenicity and mitigating immunosuppression is challenging and often associated with complicated design paradigms and immune-related adverse effects. Herein, a multienzyme-mimetic alloy nanosheet incorporating palladium (Pd) and iron (Fe) is developed, which can prime effective CIC by overcoming ferroptosis resistance for enhancing tumor immunogenicity and reprograming the tumor microenvironment for enhanced second near-infrared (NIR-II) photoimmunotherapy. The nanosheets accumulate in tumors when administered intravenously and counteract hypoxia through catalase-like oxygen production and subsequent reduction of hypoxia-inducible factor-1α, M2-like macrophages, regulatory T-cell, and programmed death-ligand 1 (PD-L1) expression. The surface plasmon resonance of the nanosheets enables NIR-II phototherapy and photoacoustic imaging, coupling with its ferroptosis and tumor microenvironment reprogram properties to synergize with anti-PD-L1 checkpoint blockade therapy to achieve satisfactory antitumor outcome. This study offers a strategy for localized tumor treatment and boosting the CIC through a straightforward and inexpensive nanomaterial design.

Mitochondrial-uncoupling nanomedicine for self-heating and immunometabolism regulation in cancer cells

Developing endogenous hyperthermia offers a promising strategy to address challenges with current exogenous hyperthermia techniques in clinics. Herein, a CD44-targeted and thermal-responsive nanocarrier was developed for the simultaneous delivery of 2,4-dinitrophenol and syrosingopine. The objective was to induce endogenous hyperthermia and regulate immunometabolism, ultimately augmenting anti-tumour immune responses. Dinitrophenol as mitochondrial uncoupler can convert electrochemical potential energy of inner mitochondrial membrane into heat, facilitating endogenous hyperthermia. Meanwhile, syrosingopine not only inhibits excessive lactate efflux caused by dinitrophenol but also downregulates tumour cell glycolysis, thus alleviating immunosuppression and heat shock protein (HSP)-dependent thermo-resistance through immunometabolism regulation. The synergistic effects of endogenous hyperthermia and immunometabolism regulation by this nanomedicine have potential to enhance tumor immunogenicity, reshape the tumour immune microenvironment, and effectively suppress the growth of subcutaneous tumours and patient-derived organoids in triple-negative breast cancer. Therefore, the endogenous hyperthermia strategy developed in this study would revolutionize hyperthermia for cancer treatment.

Cancer cell-intrinsic biosynthesis of itaconate promotes tumor immunogenicity

The Krebs cycle byproduct itaconate has recently emerged as an important metabolite regulating macrophage immune functions, but its role in tumor cells remains unknown. Here, we show that increased tumor-intrinsic cis-aconitate decarboxylase (ACOD1 or CAD, encoded by immune-responsive gene 1, Irg1) expression and itaconate production promote tumor immunogenicity and anti-tumor immune responses. Furthermore, we identify thimerosal, a vaccine preservative, as a specific inducer of IRG1 expression in tumor cells but not in macrophages, thereby enhancing tumor immunogenicity. Mechanistically, thimerosal induces itaconate production through a ROS-RIPK3-IRF1 signaling axis in tumor cells. Further, increased IRG1/itaconate upregulates antigen presentation-related gene expression via promoting TFEB nuclear translocation. Intratumoral injection of thimerosal induced itaconate production, activated the tumor immune microenvironment, and inhibited tumor growth in a T cell-dependent manner. Importantly, IRG1 deficiency markedly impaired tumor response to thimerosal treatment. Furthermore, itaconate induction by thimerosal potentiates the anti-tumor efficacy of adoptive T-cell therapy and anti-PD1 therapy in a mouse lymphoma model. Hence, our findings identify a new role for tumor intrinsic IRG1/itaconate in promoting tumor immunogenicity and provide a translational means to increase immunotherapy efficacy.

Ionizable STING-Activating Nanoadjuvants Enhance Tumor Immunogenicity and Potentiate Immunotherapy Efficacy in Solid Tumors.

Therapeutic strategies that induce inflammatory responses in immunologically "cold" tumors have the potential to improve immunotherapeutic outcomes. Pharmacologically activating the stimulator of interferon gene (STING) pathway induces innate immunity, subsequently enhancing tumor immunogenicity. Here, we developed a nanoadjuvant with tumor-restricted pharmacology that rapidly activated STING and reshaped the tumor microenvironment. The non-nucleotide STING agonist MSA-2 was chemically engineered with a piperazine motif linked by a saturated hydrocarbon chain of varying lengths to produce ionizable prodrugs that were further developed into nanoadjuvants. Compared with state-of-the-art liposomes, the nanoadjuvant displayed prolonged retention in the circulation and improved intratumoral delivery. In the acidic tumor microenvironment, the nanoadjuvant underwent polyethylene glycol deshielding, enabling efficient extravasation and penetration into tumors. Concomitantly, the STING prodrug escaped from the endo/lysosome compartment to partition into the cytosol for spontaneous esterase-catalyzed drug activation. In mouse models of syngeneic and chemically induced colorectal cancers, nanoparticle treatment provoked robust STING-mediated antitumor immunity, shifting the tumor immune landscape from immunosuppressed to tumoricidal. Additionally, the nanoadjuvant demonstrated antitumor efficacy in triple-negative breast cancer, which was further enhanced by the addition of immune checkpoint inhibitors. Collectively, this study demonstrates the safety and immune-stimulating effects of a STING-activating nanoadjuvant, supporting the clinical evaluation of this STING immunotherapeutic alone and in combination with other immunotherapies. Significance: STING-activating nanoadjuvants rationally engineered using an ionizable prodrug approach for systemic administration are well-tolerated and yield durable antitumor immune responses, providing a potential immunotherapeutic strategy to improve cancer treatment.

Tuning Immune-Cold Tumor by Suppressing USP10/B7-H4 Proteolytic Axis Reinvigorates Therapeutic Efficacy of ADCs.

Tuning immune-cold tumor hot has largely attracted attention to improve cancer treatment, including immunotherapy and antibody-drug conjugates (ADCs). Utilizing multiomic analyses and experimental validation, this work identifies a pivotal role for the USP10/B7-H4 proteolytic axis in mediating the interplay between tumor immune responses and ADC efficacy, particularly for sacituzumab govitecan (SG) in treating triple negative breast cancers (TNBCs). Mechanistically, the inhibition of autocrine motility factor receptor (AMFR)-mediated ubiquitylation of B7-H4 by the deubiquitinase USP10 leads to the stabilization of B7-H4, which suppresses tumor immune activity and reduces SG treatment effectiveness. Pharmacological inhibition of USP10 promotes the degradation of B7-H4, enhancing tumor immunogenicity and consequently improving the tumor-killing efficacy of SG. In preclinical TNBC models, suppression of USP10/B7-H4 proteolytic axis is effective in increasing SG killing efficacy and reducing tumor growth, especially for the tumors with the USP10high/B7-H7high signature. Collectively, these findings uncover a novel strategy for targeting the immunosuppressive molecule B7-H4 for cancer therapy.

Gold Nano Frameworks with Mesopores for Synergistic Immune-Thermal Therapy in Hepatic Carcinoma: A Paradigm Shift in Immune Checkpoint Blockade.

Immune checkpoint blockade (ICB) therapy, while showing promise in various cancers, exhibits limited effectiveness in hepatic carcinoma due to the tumor's immunosuppressive microenvironment (TME) and challenges associated with immune cell infiltration. Efforts to transform the "cold" TME into an "inflamed" state, notably through chemo-immunotherapy, have sparked interest due to their potential to induce immunogenic cell death and augment the infiltration of cytotoxic T lymphocytes (CTLs). Nonetheless, the efficacy of chemo-immunotherapy is often compromised by suboptimal pharmacokinetics, poor tumor accumulation, and off-target toxicity. Herein, in response, we introduce an innovative, milder thermal therapeutic approach leveraging gold nano frameworks with mesopores for the targeted delivery of the immunostimulant imiquimod and NIR-II photothermal therapy. This strategy employs targeted molecule modifications to ensure precise tumor targeting, guided by photoacoustic imaging. Subsequent to mild thermal treatment, there is a release of immunogenic proteins (CRT and HSP90), enhancing tumor immunogenicity. Assisted by imiquimod, substantial CTL infiltration occurs, accompanied by pro-inflammatory factor release (TNF-α, IL-6), transforming M2 macrophages into the M1 phenotype. Ultimately, the proposed strategy combines PD-L1/PD-1 blockade, imiquimod and mild thermal treatment to synergistically enhance tumor immunogenicity, remodel the TME, and restrain hepatic carcinoma, making strides in ICB synergistic immune-thermal therapy.

Metal-Phenolic Vehicles Potentiate Cycle-Cascade Activation of Pyroptosis and cGAS-STING Pathway for Tumor Immunotherapy.

The treatment of triple-negative breast cancer (TNBC) faces challenges due to its limited immune response and weak tumor immunogenicity. A collaborative strategy involves combining the activation of pyroptosis and the stimulator of interferon genes (STING) pathway to enhance tumor immunogenicity and fortify the antitumor immune response, which may improve therapeutic outcomes in TNBC. In this study, we report the fabrication of a zinc-phenolic nanocapsule (RMP@Cap), which is loaded with mitoxantrone (MTO) and anti-PD-L1 antibodies (aPD-L1) and coated with erythrocyte membrane, for TNBC immunotherapy. The delivery of RMP@Cap can induce tumor cell pyroptosis and, therefore, trigger the release of mitochondrial DNA, which further combines with zinc agonists to intensify STING activation, resulting in a cascade amplification of the therapeutic effect on tumors. Additionally, the incorporation of aPD-L1 into the zinc-phenolic nanocapsule relieves the inhibitory effect of tumor cells on recruited cytotoxic T cells, thereby improving the tumor-killing capacity. Furthermore, the incorporation of a camouflaged erythrocyte membrane coating enables nanocapsules to achieve prolonged in vivo circulation, resulting in improved tumor accumulation for effective antitumor therapy. This study demonstrates a synergistic therapeutic modality involving pyroptosis, coupled with the simultaneous activation and cyclic amplification of the STING pathway in immunotherapy.

Nilotinib boosts the efficacy of anti-PDL1 therapy in colorectal cancer by restoring the expression of MHC-I

BackgroundAlthough immune checkpoint inhibitors (ICIs) have revolutionized the landscape of cancer treatment, only a minority of colorectal cancer (CRC) patients respond to them. Enhancing tumor immunogenicity by increasing major histocompatibility complex I (MHC-I) surface expression is a promising strategy to boost the antitumor efficacy of ICIs.MethodsDual luciferase reporter assays were performed to find drug candidates that can increase MHC-I expression. The effect of nilotinib on MHC-I expression was verified by dual luciferase reporter assays, qRT-PCR, flow cytometry and western blotting. The biological functions of nilotinib were evaluated through a series of in vitro and in vivo experiments. Using RNA-seq analysis, immunofluorescence assays, western blotting, flow cytometry, rescue experiments and microarray chip assays, the underlying molecular mechanisms were investigated.ResultsNilotinib induces MHC-I expression in CRC cells, enhances CD8+ T-cell cytotoxicity and subsequently enhances the antitumor effects of anti-PDL1 in both microsatellite instability and microsatellite stable models. Mechanistically, nilotinib promotes MHC-I mRNA expression via the cGAS-STING-NF-κB pathway and reduces MHC-I degradation by suppressing PCSK9 expression in CRC cells. PCSK9 may serve as a potential therapeutic target for CRC, with nilotinib potentially targeting PCSK9 to exert anti-CRC effects.ConclusionThis study reveals a previously unknown role of nilotinib in antitumor immunity by inducing MHC-I expression in CRC cells. Our findings suggest that combining nilotinib with anti-PDL1 therapy may be an effective strategy for the treatment of CRC.

Breast Cancer Treatment Strategies Targeting the Tumor Microenvironment: How to Convert "Cold" Tumors to "Hot" Tumors.

Breast cancer characterized as "cold tumors" exhibit low levels of immune cell infiltration, which limits the efficacy of conventional immunotherapy. Recent studies have focused on strategies using nanotechnology combined with tumor microenvironment modulation to transform "cold tumors" into "hot tumors". This approach involves the use of functionalized nanoparticles that target and modify the tumor microenvironment to promote the infiltration and activation of antitumor immune cells. By delivering immune activators or blocking immunosuppressive signals, these nanoparticles activate otherwise dormant immune responses, enhancing tumor immunogenicity and the therapeutic response. These strategies not only promise to increase the response rate of breast cancer patients to existing immunotherapies but also may pave new therapeutic avenues, providing a new direction for the immunotherapy of breast cancer.

NIR-responsive CN-Pt-GEM hydrogel induces necroptosis and immunotherapeutic responses prevent postoperative recurrence and wound infection in lung carcinoma

BackgroundCancer recurrence following surgical resection is a major cause of treatment failure. Finding effective methods to prevent postoperative recurrence and wound infection is an important component of successful surgery. With the development of new nanotechnology, more treatment options have been provided for postoperative adjuvant therapy. This study presents an innovative hydrogel system that stimulates tumoricidal immunity after surgical resection of non-small cell lung cancer (NSCLC) and prevents cancer relapse.ResultsThe hydrogel system is based on the excellent photothermal conversion performance of single-atom platinum (CN-Pt) along with the delivery and release of the chemotherapy drug, gemcitabine (GEM). The system is coated onto the wound surface after tumor removal with subsequent near-infrared (NIR) photothermal therapy, which efficiently induces necroptosis of residual cancer cells, amplifies the levels of damage-associated molecular patterns (DAMPs), and increases the number of M1 macrophages. The significantly higher levels of phagocytic macrophages enhance tumor immunogenicity and sensitize cancer cells to CD8 + T-cell immunity to control postoperative recurrence, which has been verified using an animal model of postoperative lung cancer recurrence. The CN-Pt-GEM-hydrogel with NIR can also inhibit postoperative wound infection.ConclusionsThese findings introduce an alternative strategy for supplementing antitumor immunity in patients undergoing resection of NSCLC tumors. The CN-Pt-GEM-hydrogel with the NIR system also exhibits good biosafety and may be adaptable for clinical application in relation to tumor resection surgery, wound tissue filling, infection prevention, and recurrence prevention.

Nano-Delivery of Immunogenic Cell Death Inducers and Immune Checkpoint Blockade Agents: Single-Nanostructure Strategies for Enhancing Immunotherapy.

Cancer immunotherapy has revolutionized oncology by harnessing the patient's immune system to target and eliminate cancer cells. However, immune checkpoint blockades (ICBs) face limitations such as low response rates, particularly in immunologically 'cold' tumors. Enhancing tumor immunogenicity through immunogenic cell death (ICD) inducers and advanced drug delivery systems represents a promising solution. This review discusses the development and application of various nanocarriers, including polymeric nanoparticles, liposomes, peptide-based nanoparticles, and inorganic nanoparticles, designed to deliver ICD inducers and ICBs effectively. These nanocarriers improve therapeutic outcomes by converting cold tumors into hot tumors, thus enhancing immune responses and reducing systemic toxicity. By focusing on single-nanoparticle systems that co-deliver both ICD inducers and ICBs, this review highlights their potential in achieving higher drug concentrations at tumor sites, improving pharmacokinetics and pharmacodynamics, and facilitating clinical translation. Future research should aim to optimize these nanocarrier systems for better in vivo performance and clinical applications, ultimately advancing cancer immunotherapy.

Serine Depletion Promotes Antitumor Immunity by Activating Mitochondrial DNA-Mediated cGAS-STING Signaling.

Serine is critical for supporting cancer metabolism, and depriving malignant cells of this nonessential amino acid exerts antineoplastic effects, in large part, through disrupting metabolic pathways. Given the intricate relationship between cancer metabolism and the immune system, the metabolic defects imposed by serine deprivation might impact tumor-targeting immunity. In this study, we demonstrated that restricting endogenous and exogenous sources of serine in colorectal cancer cells results in mitochondrial dysfunction, leading to mitochondrial DNA (mtDNA) accumulation in the cytosol and consequent cGAS-STING1-driven type I IFN secretion. Depleting mtDNA or blocking its release attenuated cGAS-STING1 activation during serine deprivation. In vivo studies revealed that serine deprivation limits tumor growth, accompanied by enhanced type I IFN signaling and intratumoral infiltration of immune effector cells. Notably, the tumor-suppressive and immune-enhancing effects of serine restriction were impaired by T-cell depletion and IFN receptor blockade. Moreover, disrupting cGAS-STING1 signaling in colorectal cancer cells limited the immunostimulatory and tumor-suppressive effects of serine deprivation. Lastly, serine depletion increased the sensitivity of tumors to an immune checkpoint inhibitor targeting PD-1. Taken together, these findings reveal a role for serine as a suppressor of antitumor immunity, suggesting that serine deprivation may be employed to enhance tumor immunogenicity and improve responsiveness to immune checkpoint inhibitors. Significance: Depriving cancer cells of serine provokes mitochondrial perturbations that induce cytosolic mitochondrial DNA accumulation and subsequent activation of cGAS-STING signaling, stimulating tumor-targeting immune responses that can be enhanced with PD-1 targeted therapy. See related commentary by Borges and Garg, p. 2569.