Tumor‐Penetrating Nanotherapeutics Loading a Near‐Infrared Probe Inhibit Growth and Metastasis of Breast Cancer

The tumor growth and metastasis is the leading reason for the high mortality of breast cancer. Herein, it is first reported a deep tumor‐penetrating photothermal nanotherapeutics loading a near‐infrared (NIR) probe for potential photothermal therapy (PTT) of tumor growth and metastasis of breast cancer. The NIR probe of 1,1‐dioctadecyl‐3,3,3,3‐tetramethylindotricarbocyanine iodide (DiR), a lipophilicfluorescent carbocyanine dye with strong light‐absorbing capability, is entrapped into the photothermal nanotherapeutics for PTT application. The DiR‐loaded photothermal nanotherapeutics (DPN) is homogeneous nanometer‐sized particles with the mean diameter of 24.5 ± 4.1 nm. Upon 808 nm laser irradiation, DPN presents superior production of thermal energy than free DiR both in vitro and in vivo. The cell proliferation and migration activities of metastatic 4T1 breast cancer cells are obviously inhibited by DPN in combination with NIR irradiation. Moreover, DPN can induce a higher accumulation in tumor and penetrate into the deep interior of tumor tissues. The in vivo PTT measurements indicate that the growth and metastasis of breast cancer are entirely inhibited by a single treatment of DPN with NIR irradiation. Therefore, the deep tumor‐penetrating DPN can provide a promising strategy for PTT of tumor progression and metastasis of breast cancer.     

Rational Design of Tumor Microenvironment‐Activated Micelles for Programed Targeting of Breast Cancer Metastasis

The poor drug delivery to primary and metastatic tumors of breast cancer remains a great challenge for effective antimetastasis therapy. Herein, a tumor microenvironment‐activated cabazitaxel micelles decorated with legumain‐specific melittin (TCM‐legM) are rationally designed for programed targeting of breast cancer metastasis. TCM‐legM is quiescent in blood circulation, but can be specifically activated by the highly expressed legumain in tumor microenvironments to improve their specific targeting and deep penetrating to primary or metastatic tumors. Thereafter, the activated TCM‐legM can be efficiently internalized by cancer cells and motivate the rapid pH‐responsive drug release for antimetastasis therapy. In metastatic 4T1 breast cancer cells, TCM‐legM presents significant inhibition on the proliferation, migration, and invasion activities. In vivo, TCM‐legM can be effectively delivered to both primary and metastatic tumors of breast cancer with deep tumor penetration and efficient cellular internalization, thereby resulting in a notable reduction of tumor growth and producing a 93.4% suppression of lung metastasis. Taken together, the rationally designed TCM‐legM can provide an intelligent drug delivery strategy to enhance the medical performance on treating breast cancer metastasis.     

Albumin Biomimetic Nanocorona Improves Tumor Targeting and Penetration for Synergistic Therapy of Metastatic Breast Cancer

The synergistic combination of photothermal and RNA interference therapy demonstrates great potential for effective treatment of metastatic breast cancer, but their efficacy is limited by the poor delivery efficiency to tumor. Herein, it is reported that an albumin biomimetic nanocorona (DRI‐S@HSA) can accomplish the high accumulation and deep penetration within tumor tissues, thereby holding great promise for synergistic therapy. DRI‐S@HSA is prepared by camouflaging human serum albumin (HSA) onto an IR‐780 and small interfering RNA‐loaded cell‐penetrating peptide nanoassembly (DRI‐S). In metastatic 4T1 breast cancer cells, DRI‐S@HSA can be largely internalized, and cause significant inhibition on cell migration and proliferation in combination with laser irradiation. Surprisingly, in vivo, the albumin camouflage in DRI‐S@HSA produces a 2.5‐fold enhancement on tumor accumulation compared to the undecorated DRI‐S, and dramatically improves the deep penetration capacity in tumor mass. Moreover, a single DRI‐S@HSA treatment plus 808 nm laser irradiation results in an 83.6% inhibition on tumor growth and efficient prevention of lung metastases. Taken together, the findings can provide an encouraging biomimetic tumor‐targeted drug delivery strategy to inhibit tumor progression and prevent lung metastases of breast cancer.     

Artificial Immunogenic Cell Death Lipid Nanoparticle Functions as a Therapeutic Vaccine for Cancer

Anticancer drug-mediated induction of immunogenic cell death (ICD) blocks metastasis or recurrence in cancer cells by promoting specific immune activity against cancer antigens. However, this strategy has failed to afford adequate treatment efficiency. Overcoming the failure of ICD-mediated cancer therapy, lipid nanoparticles (LNPs) containing cancer cell surface proteins are synthesized using sonication and extrusion without microfluidics. In addition, these LNPs are decorated with high-mobility group box 1 protein and calreticulin, indicators of ICD, and named artificial ICD LNPs (AiLNPs). Administration of AiLNPs effectively targets dendritic cells (DCs) and induces DC activation in mice. Moreover, treating CT-26 tumor-bearing mice with AiLNPs inhibits tumor growth by inducing CT-26 antigen-specific T-cell immunity. Furthermore, AiLNPs containing Lewis lung carcinoma (LLC1) membrane proteins can prevent metastatic LLC1 tumor growth in the lung via LLC1 antigen-specific T-cell activation. Finally, AiLNPs synthesized with human breast cancer membrane proteins activate DC-mediated antigen-specific T-cell immunity, effectively killing tumor cells. Therefore, AiLNPs are expected to be developed as a patient-specific cancer treatment to prevent cancer recurrence and metastasis.     

Emerging Approaches of Cell‐Based Nanosystems to Target Cancer Metastasis

Cancer metastasis accounts for the high mortality of cancer‐related deaths and the therapy is greatly challenged by the limited drug delivery efficiency. Inspired by the essential role of culprit cancer cells and versatile accessory cells during cancer metastasis, diverse cell‐based nanosystems (CBNs) are emerging as attractive and encouraging drug delivery platforms to target cancer metastasis. Herein, the authors focus on the emerging strategies of versatile CBNs that synergistically combine the merit of source cells and nanoparticles for antimetastasis therapy. CBNs are usually comprised of natural nanosized vesicles, cell membrane camouflaged nanoparticles, and bioengineered living cell vehicles. The authors discuss the rationality and advances of various CBNs in targeting different stages of cancer metastasis, including primary tumor, circulating tumor cells (CTCs), and distant metastasis as well as the tumor immune microenvironments (TIM). On this basis, this review provides some feasible perspectives on designing CBNs to enhance the drug delivery efficiency for treating cancer metastasis.     

Histone Deacetylase-Triggered Self-Immolative Peptide-Cytotoxins for Cancer-Selective Drug Delivery

Precise delivery and release of therapeutics in the subcellular targets are critical for tumor-selective chemotherapy. Self-immolative structures are sophisticatedly designed to achieve stimuli-responsive drug delivery. Herein, the facile fabrication of self-immolative peptide-camptothecin (CPT) nanoassemblies is reported for cancer-selective drug delivery by utilizing the dual-mode peptide targeting design and amine-catalyzed intramolecular hydrolysis. The dual-mode peptide targeting design is realized by co-assembly of tumor targeting and nuclei-localizing peptide-CPT prodrugs, rendering the nanoassemblies with efficient cancer cell-selective capability. When the nanoassemblies enter cancer cell, the overexpressed endonuclear histone deacetylases (HDACs) cleave the acetyl group to generate primary amines, triggers amine-catalyzed intramolecular hydrolysis, and fast-release drug in the cell nuclei. The peptide-CPT prodrugs release up to 68% CPT in 1 h in the presence of HDACs, while no detectable CPT release is observed in the absence of HDACs at the same time. The peptide-CPT prodrugs selectively kill cancer cells with high HDACs levels. The dual targeting peptide-CPT nanoassemblies exhibit extended blood circulation, excellent tumor accumulation, and potent antitumor activity by inhibiting tumor progression and metastasis in mice bearing 4T1 aggressive breast tumors. Overall, the HDAC-triggered self-immolative strategy is promising for developing cancer-selective drug delivery systems.     

Human Platelet Membrane Functionalized Microchips with Plasmonic Codes for Cancer Detection

The possibility of functional roles played by platelets in close alliance with cancer cells has inspired the design of new biomimetic systems that exploit platelet–cancer cell interactions. Here, the role of platelets in cancer diagnostics is leveraged to design a microfluidic platform capable of detecting cancer‐derived extracellular vesicles (EVs) from ultrasmall volumes (1 µL) of human plasma samples. Further, the captured EVs are counted by direct optical coding of plasmonic nanoprobes modified with EV‐specific antibodies. Owing to the inherent properties of platelets for multifaceted interaction with cancer cells, the microfluidic chip equipped with a biologically interfaced platelet membrane‐cloaked surface (denoted “PLT‐Chip”) can capture a significantly higher number of EVs from multiple types of cancer cell lines (prostate, lung, bladder, and breast) than the normal cell‐derived EVs. Furthermore, this chip allows the monitoring of the growth of tumor spheroids (100 µm–2.5 mm) and clearly distinguishes the plasma of cancer patients from that of normal healthy controls. This robust, multifaceted, and cancer‐specific binding affinity, coupled with excellent biocompatibility, is a unique feature of platelet membrane‐cloaked surfaces, which therefore represent promising alternatives to antibodies for application in EVs‐based cancer theranostics.     

Biomimetic Nanomedicine Coupled with Neoadjuvant Chemotherapy to Suppress Breast Cancer Metastasis via Tumor Microenvironment Remodeling

The biomimetic enzyme activity of cerium oxide nanoparticles (CeNPs) prefers ultrasmall particle size and bare surface. Unfortunately, those two features are not favorable for its in vivo application due to easy aggregation and fast renal filtration. To take advantage of the activity of CeNP for cancer therapy, a homologous targeted cerium oxide nanoparticle system, targeted CeNP (T-CeNP), with the integration of a biodegradable dendritic mesoporous silica nanoparticle, superoxide dismutase and catalase mimicking CeNPs, and the camouflage coating of cancer cell membrane has been developed. Attributed to the homologous targeting effect of cancer cell membrane, nanoparticles with camouflage coating are retained in the tumor in an orthotopic breast cancer metastatic model. Subsequently, T-CeNP effectively hinders cancer-associated fibroblast transdifferentiation and reprograms it back to a normal fibroblast. Consequently, T-CeNP coupled with doxorubicin reduces the size of primary tumors and prevents the post-surgery lung metastasis and liver metastasis of breast cancer.     

Ly6Chi Monocytes Delivering pH‐Sensitive Micelle Loading Paclitaxel Improve Targeting Therapy of Metastatic Breast Cancer

Many immune cells are capable of homing to sites of disease and eradicating infections and abnormal cells. However, their efficacy is usually down‐regulated in tumor microenvironments and it is difficult to boost. It is presumed that the anticancer activity of immune cells can be improved by integrating an additional therapeutic modality such as chemotherapy into the cells. Here, Ly6C^hi monocytes armed with the paclitaxel (PTX)‐loading pH‐sensitive micelle (PM), termed as PM@MC, are prepared. The PM internalization does not significantly affect the properties of the host Ly6C^hi monocytes. In the 4T1 metastatic breast cancer mice model, PM@MCs home to both primary tumor and the lung metastasis foci. PM@MC exhibit 15‐fold higher intratumor PTX accumulation than the commercial PTX injection, and achieve a tumor inhibiting rate of 96.8% and a lung metastasis suppression rate of 99.2%. No significant change is recorded in histology of major organs and in hematological and biochemical parameters after PM@MC treatment. The pH‐sensitive micelle/Ly6C^hi monocyte drug delivery device thus has the application potential in the targeting therapy of breast cancer with metastasis.     

Oxygen-Evolving Manganese Ferrite Nanovesicles for Hypoxia-Responsive Drug Delivery and Enhanced Cancer Chemoimmunotherapy

Immunological tolerance induced by the hypoxic tumor microenvironment has been a major challenge for current immune checkpoint blockade therapies. Here, a hypoxia-responsive drug delivery nanoplatform is reported to promote chemoimmunotherapy of cancer by overcoming the hypoxia-induced immunological tolerance of tumors. The nanovesicles are assembled from manganese ferrite nanoparticles (MFNs) grafted with hypoxia-responsive amphiphilic polymers as the membrane, with doxorubicin hydrochloride (Dox) loaded in the aqueous cavities. Under hypoxic conditions in tumors, the nanovesicles can rapidly dissociate into individual MFNs to release Dox and induce decomposition of tumor endogenous H₂O₂ for tumor hypoxia relief. As a result, the Dox-loaded nanovesicles display remarkable suppression of primary tumor growth in combination with αPD-L1-mediated checkpoint blockade therapy. Furthermore, the modulation of the hypoxic tumor microenvironment facilitates a long-lasting immunological memory effect to prevent tumor recurrence and metastasis. Therefore, this hypoxia-responsive nanoplatform presents a potential strategy for both local tumor treatment and long-term protection against tumor recurrence.     

Multiantigenic Nanoformulations Activate Anticancer Immunity Depending on Size

Nanoparticle‐adjuvanted cancer vaccines are attracting increasing attention because they can induce an effective anticancer immune response. Single‐antigen vaccines are inefficient to inhibit cancer progression due to the heterogeneity of tumors and the antigenicity alteration of tumor‐associated antigens. Therefore, the efficient delivery of multiple antigens to antigen‐presenting cells is an excellent opportunity for strong anticancer immunity. In this study, three immunoadjuvant‐loaded multiantigenic nanoparticles MANPs/R837 with different diameters, i.e., 83, 103, and 122 nm, are prepared through coating of the cancer cell membrane as a source of multiple antigens onto the imiquimod R837‐loaded poly(lactic‐co‐glycolic acid) nanoparticles. The MANP/R837 with a diameter of 83 nm (MANP83/R837) shows the most efficient delivery of the payload to the draining lymph nodes and achieves the best antigen presentation to T lymphocytes. Compared with the other two nanovaccines, MANP83/R837 has a stronger inhibitory effect on tumor growth and metastasis. In the combination therapy with checkpoint blockade therapy using programmed cell death‐1 antibody, MANPs/R837 show effective inhibition against tumor progression, and MANP83/R837 achieves the most exciting effect. Therefore, MANPs/R837, as a promising therapeutic cancer vaccine, demonstrates great prospects in cancer immunotherapy.     

Light‐Activatable Assembled Nanoparticles to Improve Tumor Penetration and Eradicate Metastasis in Triple Negative Breast Cancer

Triple‐negative breast cancer (TNBC) is a kind of aggressive malignancy with fast metastatic behavior. Herein, a nanosystem loaded with a near‐infrared (NIR) agent is developed to achieve chemo‐photothermal combination therapy for inhibiting tumor growth and metastasis in TNBC. The NIR agent of ultrasmall sized copper sulfide nanodots with strong NIR light‐absorbing capability is entrapped into the doxorubicin‐contained temperature‐sensitive polymer‐based nanosystem by a self‐assembled method. The temperature sensitive nanoclusters (TSNCs) can significantly enhance the drug penetration depth and significantly kill the cancer cells under the near‐infrared laser irradiation. Importantly, it is plausible that the tumor penetrating nanosystem combined with NIR laser irradiation can prevent lung and liver metastasis via extermination of the cancer stem cells. The in vivo characteristics, evaluated by photoacoustic imaging, pharmacokinetics, and biodistribution, confirm their feasibility for tumor treatment owing to their long blood circulation time and high tumor uptake. Thanks to the high tumor uptake and highly potent antitumor efficacy, the doxorubicin‐induced cardiotoxicity can be avoided when the TSNC is used. Taken together, it is believed that the nanosystem has excellent potential for clinical translation.     

Ternary Regulation of Tumor Microenvironment by Heparanase-Sensitive Micelle-Loaded Monocytes Improves Chemo-Immunotherapy of Metastatic Breast Cancer

Tumor immunotherapy approaches such as programmed cell death-1/programmed cell death-ligand 1 (PD-1/PD-L1) checkpoint blockade and indoleamine 2,3-dioxygenase (IDO) inhibition are proven to promote immune response against tumors. Unfortunately, their positive response rates are unsatisfactory due to complicated immunosuppressive mechanisms in the tumor microenvironment, which can probably be rescued by integrating multiple immunoregulators and chemotherapeutic agents together. To improve the combination therapy of metastatic breast cancer, a ternary heparanase (Hpa)-sensitive micelle-loaded monocyte delivery system, termed as HDNH@MC, is designed, exploiting the capacity of Ly6C^hi monocytes to be recruited to tumor sites and the overexpression of Hpa in tumors. The prodrugs of the chemotherapeutic agent docetaxel and IDO inhibitor NLG919 are synthesized by conjugating them on the substrate of Hpa, heparan sulfate. Then the PD-1/PD-L1 inhibitor HY19991-encapsulating prodrug micelle@Ly6C^hi monocyte system is prepared. HNDH@MC elevates drug concentrations and relieves immunosuppression in tumors of 4T1 breast carcinomas mice model, thus enhancing the infiltration and activity of CD8⁺ T cells and presenting significant anti-cancer effect. The lung metastasis is suppressed and the survival of mice is prolonged. HNDH@MC will be a promising option for treating metastatic breast cancer by synergy of tumor-targeting chemotherapy and immunotherapy.     

Sequentially Targeting Cancer-Associated Fibroblast and Mitochondria Alleviates Tumor Hypoxia and Inhibits Cancer Metastasis by Preventing “Soil” Formation and “Seed” Dissemination

Tumor metastasis is facilitated by the formation of the premetastatic niche (PMN) in destination organs and the dissemination of cancer cells detached from a primary tumor. This study reports a sequential combination strategy that exerts a profound anti-metastasis effect by inhibiting both PMN formation and cancer cell dissemination. The approach consists of (1) cancer-associated fibroblast cells (CAFs)-targeting liposome and (2) mitochondria-targeting polymer. The liposome depletes CAFs and reduces tumor stroma, leading to a significant increase in intratumoral oxygen perfusion. The polymer disrupts mitochondria aerobic respiration in cancer cells, leading to a considerable decrease in intratumoral oxygen consumption. With the complementary mechanisms, their combination drastically alleviates the hypoxia in orthotopic breast tumor and inhibits the pulmonary PMN formation by downregulating various hypoxia-induced PMN-fostering factors. In addition, the CAFs depletion by the liposome abrogates the metastasis-promoting crosstalk with cancer cells; meanwhile, mitochondria dysfunction by the polymer cuts off the energy supply that supports metastasis, together resulting in an efficient suppression of cancer cell dissemination. With the two-pronged strategy targeting these two aspects, the primary tumor is prominently inhibited, and distant metastasis is completely eradicated. This study provides a generalizable approach of sequential CAFs depletion and mitochondria disruption to combat metastatic tumors.     

Cancer Cell Membrane‐Coated Gold Nanocages with Hyperthermia‐Triggered Drug Release and Homotypic Target Inhibit Growth and Metastasis of Breast Cancer

The cell‐specific targeting drug delivery and controlled release of drug at the cancer cells are still the main challenges for anti‐breast cancer metastasis therapy. Herein, the authors first report a biomimetic drug delivery system composed of doxorubicin (DOX)‐loaded gold nanocages (AuNs) as the inner cores and 4T1 cancer cell membranes (CMVs) as the outer shells (coated surface of DOX‐incorporated AuNs (CDAuNs)). The CDAuNs, perfectly utilizing the natural cancer cell membranes with the homotypic targeting and hyperthermia‐responsive ability to cap the DAuNs with the photothermal property, can realize the selective targeting of the homotypic tumor cells, hyperthermia‐triggered drug release under the near‐infrared laser irradiation, and the combination of chemo/photothermal therapy. The CDAuNs exhibit a stimuli‐release of DOX under the hyperthermia and a high cell‐specific targeting of the 4T1 cells in vitro. Moreover, the excellent combinational therapy with about 98.9% and 98.5% inhibiting rates of the tumor volume and metastatic nodules is observed in the 4T1 orthotopic mammary tumor models. As a result, CDAuNs can be a promising nanodelivery system for the future therapy of breast cancer.     

Acetalated Dextran Nanoparticles Loaded into an Injectable Alginate Cryogel for Combined Chemotherapy and Cancer Vaccination

Vaccination represents a promising strategy for cancer therapy due to its ability to efficiently eliminate tumors from the host body and prevent their recurrence. Nevertheless, the current vaccines are still lacking efficacy. Combination therapies, such as those integrating chemotherapy with immunotherapy, represent a powerful tool to potentially circumvent this drawback. Herein, injectable alginate cryogels loaded with granulocyte‐macrophage colony‐stimulating factor and cytosine‐phosphodiester‐guanine‐rich oligonucleotides, are combined with spermine‐modified acetalated dextran nanoparticles (Sp‐AcDEX NPs), loaded with p53 activator Nutlin‐3a (Nut‐3a) for combined chemoimmunotherapy. The Sp‐AcDEX NPs are successfully loaded into the alginate cryogels and released over time. Furthermore, the delivery of the NPs from the cryogel enhances their accumulation in tumor tissue following peritumoral injection. Nut‐3a exerts toxicity towards the tumor cells and induces immunogenic cell death through the upregulation of surface calreticulin expression. Overall, this combination is a promising strategy to reduce cancer cell proliferation, induce immunogenic cell death, and accumulate drug payloads into the tumor. This approach may avoid cancer recurrence through the induction of in situ cancer vaccination mediated by antigens and danger signals released from the apoptotic cancer cells.     

CXCR4‐Enriched Nano‐Trap Targeting CXCL12 in Lung for Early Prevention and Enhanced Photodynamic Therapy of Breast Cancer Metastasis

Breast cancer metastasis is strongly correlated with CXCR4‐CXCL12 axis, in which the CXCR4 positive cancer cells are recruited to target organs rich in CXCL12. Although various agents have been developed to inhibit CXCR4, few strategies are reported for targeting and perturbation of CXCL12 to control breast cancer metastasis. Inspired by the increasing popularity of cell membrane (CM)‐derived therapeutics, herein, CXCR4‐enriched 4T1 CMs loaded with copper‐indium‐sulfide quantum dots (QDs) nanoparticles are employed as Nano‐trap to occupy CXCL12 and block breast cancer lung metastasis. CMs fused onto QDs cores faithfully inherit CXCR4 expression of the source cells. CXCR4‐upregulated Nano‐trap binds CXCL12 protein more efficiently than the CXCR4‐silenced counterparts, which effectively abrogate CXCL12‐mediated cancer cell invasion in vitro. In vivo fluorescent imaging reveals preferential distribution of Nano‐trap in lungs with abundant CXCL12 expression. Further interrogation of the in vivo efficacy finds lung metastasis is successfully delayed in breast cancer models pre‐injected with Nano‐trap, which reduces CXCL12 exposure in lung. For the already formed lung metastasis, Nano‐trap can alleviate hypoxia by regulating alpha‐smooth muscle actin, thus improving photodynamic therapy in the metastatic tumor. This proof‐of‐concept study sheds light on exploiting more functionalities of CM proteins for metastasis management.     

Injectable Scaffolds for In Vivo Programmed Macrophages Manufacture and Postoperative Cancer Immunotherapy

Cancer recurrence and metastasis after surgical resection is a vital reason of treatment failure. The modification of immune cells through implanted biomaterials is a promising postoperative immunotherapy. Herein, an injectable hydrogel scaffold loaded with engineered exosome mimetics that in vivo recruits and programs endogenous macrophages into M1 binding with anti-CD47 antibody (M1-aCD47 macrophages) for postoperative cancer immunotherapy is developed. Briefly, M1 macrophages-derived exosome mimetics co-modified with vesicular stomatitis virus glycoprotein (VSV-G) and aCD47 (V-M1EM-aCD47) are encapsulated in injectable chitosan hydrogel. Such hydrogel recruits inherent macrophages in situ and releases V-M1EM-aCD47 that programs M2 to M1-aCD47 macrophages. M1-aCD47 macrophages own dual-functions of tumor-homing and enhanced phagocytosis. They can actively target to tumor cells for delivery of aCD47 that blocks the “don't eat me” signal, thereby promoting phagocytosis of macrophages to cancer cells. Furthermore, V-M1EM-aCD47 hydrogel implanted into resection site of 4T1 breast tumor inhibits tumor recurrence and metastasis by phagocytosis of M1-aCD47 macrophages and T cell-mediated immune responses. The findings demonstrate that biomaterials can be designed in vivo to program inherent macrophages, thereby activating the innate and adaptive immune systems for prevention of postoperative tumor recurrence and metastasis.     

Drug-Eluting Shear-Thinning Hydrogel for the Delivery of Chemo- and Immunotherapeutic Agents for the Treatment of Hepatocellular Carcinoma

Hepatocellular carcinoma (HCC) is a malignant and deadly form of liver cancer with limited treatment options. Transcatheter arterial chemoembolization, a procedure that delivers embolic and chemotherapeutic agents through blood vessels, is a promising cancer treatment strategy. However, it still faces limitations, such as inefficient agent delivery and the inability to address tumor-induced immunosuppression. Here, a drug-eluting shear-thinning hydrogel (DESTH) loaded with chemotherapeutic and immunotherapeutic agents in nanocomposite hydrogels composed of gelatin and nanoclays is presented as a therapeutic strategy for a catheter-based endovascular anticancer approach. DESTH is manually deliverable using a conventional needle and catheter. In addition, drug release studies show a sustained and pH-dependent co-delivery of the chemotherapy doxorubicin (acidic pH) and the immune-checkpoint inhibitor aPD-1 (neutral pH). In a mouse liver tumor model, the DESTH-based chemo/immunotherapy combination has the highest survival rate and smallest residual tumor size. Finally, immunofluorescence analysis confirms that DESTH application enhances cell death and increases intratumoral infiltration of cytotoxic T-cells. In conclusion, the results show that DESTH, which enables efficient ischemic tumor cell death and effective co-delivery of chemo- and immunotherapeutic agents, may have the potential to be an effective therapeutic modality in the treatment of HCC.