Active initiation of plasma membrane rupture represents a promising strategy to disrupt cellular homeostasis and induce cancer cell death. This study proposes phospholipase A1 (PLA1) as a molecular “cell‐puncher” to hydrolyze phospholipids, compromising cancer cell membrane integrity and enabling uncontrolled molecular flux. PLA1 synergistically enhances the tumoradical efficacy of cholesterol oxidases (CODs) and lipoxygenases (LOXs) by liberating their respective substrates, cholesterol, and polyunsaturated fatty acids. When localized within tumors using a thermoresponsive chitosan/β‐glycerol‐phosphate hydrogel, PLA1‐COD or PLA‐LOX enzymatic pairs achieved effective treatment of CT26 murine tumors through cascading plasma membrane rupture and oxidative stress amplification. Furthermore, the hydrogel‐embedded enzyme system functioned as an injectable embolic agent, suppressing orthotopic N1S1 hepatoma in rats via transcatheter arterial enzyme embolization. This work demonstrated an enzyme‐based oncolytic strategy that targets membrane integrity and oxidative stress pathways, showing significant potential for clinical translation in solid tumor management.

Hyperthermic intraperitoneal chemotherapy (HIPEC) is widely performed for treating peritoneal malignancies, yet its clinical application remains limited by insufficient efficacies and risks in chemotherapy-associated side effects. This study demonstrates that mild hyperthermia enhances cancer cell sensitivity to hydrogen peroxide (H2O2) and Ca2+ exposure while sparing normal cells at both elevated and physiological temperatures. Mechanistically, mild hyperthermia promotes H2O2 cellular entry, synergistically activating calcium channels in the plasma membrane and endoplasmic reticulum to induce Ca2+-overload-dependent cancer cell necroptosis. Using H2O2 and Ca2+ solution as a thermo-sensitive necroptosis-inducing perfusate (TNIP), peritoneal perfusion at 43°C demonstrates stronger suppressive effects on the growth of multiple peritoneal tumors in mice compared to conventional HIPEC using various chemotherapeutics. TNIP-mediated hyperthermic intraperitoneal treatment also elicits robust antitumor immunity in syngeneic murine models, with enhanced therapeutic efficacy when combined with postoperative immune checkpoint blockade therapy. The superior immune activation capacities of this strategy are further validated in patient-derived organoids. This work establishes a chemo-free, thermo-activated immunogenic perfusion strategy to selectively trigger cancer cell necroptosis, demonstrating a translatable hyperthermic intraperitoneal immunotherapy with improved therapeutic efficacy and safety.

Abstract Radiotherapy has demonstrated broad applications in treating solid tumors, but the hostile tumor microenvironment features significantly limit its clinical outcomes by impairing the priming of systemic antitumor immune responses. In this study, we developed a pH‐responsive nanomedicine by coating calcium carbonate nanoparticles with a quercetin‐zinc coordination polymer to potentiate radiotherapy through synergistic reprogramming of the immunosuppressive tumor microenvironment. Our results demonstrated that Zn 2+ induced pyroptosis in cancer cells further improves their immunogenicity, while quercetin upon being delivered to tumor sites significantly alleviates tumor hypoxia by sequentially decreasing extracellular collagen deposition and promoting tumor perfusion. The QZCaCO 3 ‐PEG, when administered intravenously, exhibited synergistic activity with localized X‐ray irradiation, triggering robust antitumor immunity and substantially inhibiting growth in both irradiated primary tumors and non‐targeted distant lesions. Additionally, QZCaCO 3 ‐PEG combined with radiotherapy elicited a durable immune memory response, effectively suppressing tumor recurrence in multiple murine rechallenge models. This study establishes a versatile strategy for designing multifunctional pH‐responsive nanomedicine as an immunogenic nano‐radiosensitizer to amplify radiotherapy via concurrent pyroptosis induction and tumor hypoxia alleviation.

ABSTRACT Supramolecular aggregates, formed through the highly directional and reversible noncovalent assembly of building blocks, represent a cornerstone of modern materials science, enabling the creation of complex architectures with emergent properties. Among the diverse molecular platforms available, resorcin[4]arene‐derived cavitands have emerged as particularly powerful building units due to their intrinsic concave cavity, tunable geometry, and versatile functionalization capacity. This review highlights recent progress in the construction of functional supramolecular aggregates based on resorcin[4]arene cavitands, with a focus on their assembly strategies and wide‐ranging applications. The review systematically covers several key types of aggregate systems: porous coordination aggregates (e.g., metal‐organic frameworks [MOFs]) with stimuli‐responsive properties, dynamic polymeric aggregates exhibiting self‐healing behavior, sensing aggregates enabling differential detection, and therapeutic aggregates for combination therapy. These systems are unified by their exploitation of cavitands’ unique host‐guest chemistry and their ability to form well‐defined superstructures through various noncovalent interactions. We emphasize how the precise manipulation of cavitand structure directs the assembly process and dictates the functional output of the resulting aggregates. Finally, we outline current challenges and future opportunities in this field, highlighting the potential of cavitand‐based aggregates to enable next‐generation technologies in sensing, catalysis, biomedicine, and energy materials. This review is expected to provide valuable insights and inspiration for researchers working in supramolecular chemistry and aggregate science. The construction of supramolecular aggregates triggered by macrocycles has become a thriving area of supramolecular chemistry. In this context, resorcinarene cavitands, a class of macrocyclic receptors with intrinsic cavities, have been drawn into the limelight because of their advantages, such as the concave‐shaped structure, adjustable cavity size, favorable host‐guest behavior, and ease of functionalization. They can induce organic and inorganic molecules to self‐assemble into supramolecular aggregates through various bonding modes, including hydrophobic interactions, metal‐ligand coordination, van der Waals forces, hydrogen bonding, electrostatic interactions, π‐π stacking, and amphiphilic interactions. This minireview focuses on some representative resorcinarene cavitand‐based assembly aggregates, including microporous MOFs, supramolecular polymers, sensor arrays, and multifunctional nanodrugs. Each section highlights recent advancements, structural characteristics, and functional applications of these aggregate systems. This review will provide useful information for researchers working on not only cavitand chemistry but also the chemistry of other macrocyclic hosts, and it will inspire new discoveries in the field of supramolecular assemblies and systems containing macrocyclic hosts.

Non-covalent molecular capsules stand as a central research theme in the field of supramolecular chemistry. Characterized by their dynamic confined architectures assembled through non-covalent interactions, including hydrogen bonding and electrostatic interaction, these capsules hold significant promise for applications in catalysis, medicine, and materials science. Conventionally, the construction of molecular capsules has predominantly depended on pre-embedded complementary motifs within supramolecular hosts, a limitation that restricts their synthetic versatility and adaptability. This study addresses this challenge by presenting the design and synthesis of a water-soluble 2-aminobenzimidazole-functional-ized cavitand 1, which is based on a resorcin[4]arene framework. And we examined the binding of the homologous series of the n-alkanes (n-C7H16 to n-C(2)0H(42)) to cavitand 1 using a combination of H-1 NMR spectroscopy (nuclear magnetic resonance spectroscopy), 2D NOESY (two-dimensional Nuclear Overhauser Effect Spectroscopy) and DOSY (diffusion ordered spectroscopy) experiments. Cavitand 1 can form 1:1 complexes with n-C7H16 and n-C10H22, and no encapsulation behavior for n-C11H24 because the size of n-C11H24 is too large to form 1:1 complex and too small to form a dimeric capsule. n-C12H26 to n-C(2)0H(42) are good templates for the formation of 1:2 guest-host capsular complexes. The guest of n-C12H26 fits the space comfortably in an extended conformation and broadened, symmetrical signal patterns were observed in the 1H NMR spectrum. For n-C15H32 the signals are sharper suggesting a kinetically more stable complex. The conformation of n-C15H32 inside the capsule was determined by 2D NOESY experiments. Cross-peaks between the hydrogen atoms at C(1) and C(3) and at C(1) and C(4), C(2) and C(4) and at C(2) and C(5) were observed. But C(6) is in NOE contact only with C(8). This demonstrates the presence of gauche conformations of four carbon atoms at the ends and an extended chain of carbon atoms in the middle. n-C7H16 subset of 1 is a 1:1 complex and n-C15H32 subset of 1.1 is a dimeric capsule confirmed by DOSY experiments which reveal diffusion coefficients for n-C7H16 subset of 1 (D=2.02x10(-6) cm(2).s(-1)) and n-C15H32 subset of 1.1 (D=1.54x10(-6) cm(2).(s-1)). Through the Stokes-Einstein relationship, show that the hydrodynamic volume of n-C15H32 subset of 1.1 is 2.3 times that of n-C7H16 subset of 1. Then we investigated host-guest interactions between cavitand 1 and styrylpyridinium SP-Cn (n=1 similar to 10) fluorophores in solution using H-1 NMR and UV-Vis absorption spectra. The results indicate that a supramolecular nano-capsule structure was formed with a 2:1 host-guest stoichiometric ratio (SP-Cn subset of 1.1). The electron-poor pyridinium group of SP-Cn is bound within the electron-rich cavity through cation center dot center dot center dot pi interactions. Hydrophobic effects and C-H center dot center dot center dot pi hydrogen bonds drive two cavitand 1 to form a capsule. And the alkyl chain of SP-C10 was compressed to J-shaped conformation by the restricted space. SP-C1 subset of 1. 1 exhibits strong fluorescence in water due to the suppression of aromatic ring rotation within the confined space. Overall, the formation of these molecular capsules is primarily driven by the synergistic action of hydrophobic interactions and C-H center dot center dot center dot pi interactions, providing new insights into the rational design of supramolecular assemblies.

The realization of tumor infarction therapy through the induction of tumor-localized thrombosis is an appealing cancer treatment strategy, but its therapeutic potency is severely hindered by posttreatment tumor relapse, which mainly results from incomplete intravascular thrombosis. Herein, a pH-responsive nanoreactor (coined as TLCaP2 NRs) is designed by enveloping thrombin and lipoxygenase within poly(ethylene glycol)-b-poly(glutamic acid) copolymeric micelles through the biomineralization growth of calcium phosphate. Thrombin is adopted to occupy tumor blood vessels through inducing intravascular blood clots, the polyunsaturated fatty acids of which are synergistically converted to cytotoxic lipid radicals by lipoxygenase and the released hemoglobin to induce ferroptotic cancer cell death. Upon tumor accumulation, TLCaP2 NRs could inhibit the growth of both CT26 and H22 tumors in mice through the enzymatic promotion of tumor-localized intravascular thrombosis and lipid peroxidation. Moreover, via the doping of Mn2+, which can activate the cyclic GMP-AMP synthase-stimulator of interferon genes pathway, the yielded TLCaMnP2 NRs showed potent tumor suppression efficacy through the enzymatic induction of cancer cell death and the elicitation of antitumor immunity. This work highlights an ingenious strategy to prepare immunogenic nanoreactors via a biomineralization process for the enzymatic induction of intravascular thrombosis and lipid peroxidation and the priming of antitumor immunity.

Inflammatory bowel disease (IBD) such as ulcerative colitis (UC) is an autoimmune disease characterized by persistent inflammation along the gastrointestinal tract with excessive generation of reactive oxygen species (ROS)/reactive nitrogen species (RNS) generation. Here, catalase (CAT)-containing microreactor capsules with long-lasting broad-spectrum ROS/RNS-scavenging capability are developed for the treatment of IBD. In this design, CAT is encapsulated in the dense hydrogel network of calcium alginate (ALG) microspheres, which provides long-term protection of CAT activity in protease-rich intestinal environment. Afterward, the polydopamine (PDA) modification on the surface of CAT@ALG microspheres can provide them bioadhesiveness to achieve prolonged retention in the intestinal tract and broad-spectrum scavenging capability against various types of ROS/RNS beyond hydrogen peroxide. Enteric capsules are further used to protect the CAT@ALG-PDA microspheres from gastric fluid for selective release at the intestinal site. The combined action of PDA and CAT in CAT@ALG-PDA microreactors results in the broad-spectrum scavenging of excess ROS/RNS and regulates redox balance in acute UC rat model, showing satisfactory therapeutic effects superior to the mesalazine and adalimumab at clinically relevant doses without obvious side effects. This work highlights that these CAT@ALG-PDA capsules can act as long-acting broad-spectrum ROS/RNS reactors, promising for IBD treatment.

Photodynamic therapy (PDT) has been investigated for minimal invasive treatment of superficial tumors, but its clinical efficacy is constrained by its immediate light-dependent cytotoxicity, low immunogenicity, and other reasons. Building on the capacity of polyunsaturated fatty acids (PUFAs) to convert short-lived reactive oxygen species into longer-lived, highly cytotoxic lipid radicals, we develop a long-acting liposomal photosensitizer by co-encapsulating chlorin e6 (Ce6) and linoleic acid (LA) with commercial lipids. The resulting LA-Ce6@liposome converts short-lived singlet oxygens to persistent lipid radicals during light exposure, sustaining free LA peroxidation even post-irradiation. Mechanistic studies demonstrate that LA-Ce6@liposome-mediated PDT drives immunogenic ferroptosis and PANoptosis in cancer cells via amplified lipid peroxidation. In preclinical models, this strategy not only inhibits the growth of light-irradiated primary tumors but also activates systemic antitumor immunity, delaying progression of distal metastatic and rechallenged tumors, particularly when synergized with immune checkpoint blockade therapy. This study highlights a streamlined strategy to augment conventional PDT by integrating photosensitizers with PUFAs, offering prolonged tumoradical activity and immune activation.

Lead chalcohalides(PbYX,X=Cl,Br,I;Y=S,Se)is an extension of the classic Pb chalcogenides(PbY).Constructing the heterogeneous integration with PbYX and PbY material systems makes it possible to achieve significantly improved opto-electronic performance.In this work,we studied the effect of introducing halogen precursors on the structure of classical PbS nanocrystals(NCs)during the synthesis process and realized the preparation of PbS/Pb3S2X2 core/shell structure for the first time.The core/shell structure can effectively improve their optical properties.Furthermore,our approach enables the synthesis of Pb3S2Br2 that had not yet been reported.Our results not only provide valuable insights into the heterogeneous integration of PbYX and PbY materials to elevate material properties but also provide an effective method for further expanding the prepa-ration of PbYX material systems.

Radioimmunotherapy represents a clinically available combination strategy for treating a broad range of solid tumors, however, its therapeutic efficacy remains significantly compromised by tumor hypoxia due to the inhibition of cytotoxicity and the suppression of antitumor immunity activation. Herein, we synthesized a pHresponsive oxygen-releasing nanomedicine (denoted as an oxygen nanotank) by growing a thin manganese dioxide (MnO2) layer onto calcium hyperoxide (CaO2) nanoparticles through an in-situ oxidation process to enhance radioimmunotherapy. Using a two-step liposomal coating strategy, we obtained CaO2@MnO2-PEG, which exhibited excellent physiological stability, with MnO2 functioned as a catalase-like nanozyme to enable pH-dependent oxygen generation. This nanomedicine significantly enhanced the X-ray irradiation induced cytotoxicity against hypoxic tumor cells by amplifying intracellular reactive oxygen species. After intravenous injection, CaO2@MnO2-PEG specifically accumulated in tumor tissues and substantially alleviated hypoxia, resulting in enhanced therapeutic outcomes of X-ray-mediated external radiotherapy in a subcutaneous CT26 tumor model. Furthermore, combining CaO2@MnO2-PEG with immune checkpoint blockade therapy achieved synergistic tumor suppression by concurrently activating innate and adaptive immune responses. This study establishes a controllable synthesis method for pH-responsive oxygen nanotanks, effectively addressing hypoxiainduced therapeutic resistance in radioimmunotherapy.

The radiotherapy-induced release of DNA fragments can stimulate the cyclic guanosine monophosphate-adenosine monophosphate synthase-stimulator of interferon genes (cGAS-STING) pathway to prime antitumor immunity, but this pathway is expected to be less potent because of the inefficient cytosolic delivery of negatively charged DNA fragments. In this study, manganese-coordinated chitosan (CS-Mn) microparticles with selective DNA-capturing capacity are concisely prepared via a coordination-directed one-pot synthesis process to potentiate the immunogenicity of radiotherapy. The obtained CS-Mn microparticles that undergo rapid disassembly under physiological conditions can selectively bind with DNA to form positively charged DNA-CS assemblies because of the strong electrostatic interaction between linear chitosan and DNA molecules. They thus enable efficient cytosolic delivery of DNA in the presence of serum to cooperate with Mn2+ to activate the cGAS-STING pathway in dendritic cells. Upon intratumoral injection, the CS-Mn microparticles markedly enhance the efficacy of radiotherapy against both irradiated and distal tumors in different tumor models via collectively promoting tumor-infiltrating CD8+ T-cell stemness and the activation of innate immunity. The radiosensitization effect of CS-Mn microparticles can be further augmented by concurrently applying anti-programmed cell death protein 1 (anti-PD-1) immunotherapy. This work highlights an ingenious strategy to prepare Trojan horse-like DNA-capturing microparticles as cGAS-STING-activating radiosensitizers for effective radioimmunotherapy.

The efficacy of radiotherapy has not yet achieved optimal results, partially due to insufficient priming and infiltration of effector immune cells within the tumor microenvironment (TME), which often exhibits suppressive phenotypes. In particular, the infiltration of X-C motif chemokine receptor 1 (XCR1)-expressing conventional type-1 dendritic cells (cDC1s), which are critical in priming CD8+ cytotoxic T cells, within the TME is noticeably restricted. Hence, we present a facile methodology for the efficient fabrication of a calcium phosphate hydrogel loaded with X-C motif chemokine ligand 1 (XCL1) to selectively recruit cDC1s. Manganese phosphate microparticles were also loaded into this hydrogel to reprogram the TME via cGAS-STING activation, thereby facilitating the priming of cDC1s propelled specific CD8+ T cells. They also polarize tumor-associated macrophages towards the M1 phenotype and reduce the proportion of regulatory cells, effectively reversing the immunosuppressive TME into an immune-active one. The yielded XCL1@CaMnP gel exhibits significant efficacy in enhancing the therapeutic outcomes of radiotherapy, particularly when concurrently administered with postoperative radiotherapy, resulting in an impressive 60 % complete response rate. Such XCL1@CaMnP gel, which recruits cDC1s to present tumor antigens generated in situ, holds great potential as a versatile platform for enhanced cancer treatment through modulating the immunosuppressive TME.

Incomplete tumor removal after microwave ablation (MWA), a widely used hyperthermia-based therapy, can result in tumor recurrence. Herein, attenuated Salmonella typhimurium VNP20009 is engineered to release interleukin-15&interleukin-15-receptor-alpha (IL-15&IL-15R alpha) in response to mildly elevated temperature. Such 15&15R@VNP colonizes in tumors upon intravenous injection, and the expression of IL-15&IL-15R alpha is triggered by MWA. Anti-tumor immune responses are elicited, efficiently suppressing tumor growth even after incomplete microwave ablation. We further design VNP20009 with thermal-responsive co-expression of both IL-15&IL-15R alpha and soluble programmed cell death protein (sPD-1). Such sPD-1-15&15R@VNP can also reverse the functional suppression of immune cells driven by PD-1/PD-L1 axis, reinvigorating progenitor exhausted T cells, a critical subset of cytotoxic T lymphocytes responsive to immune checkpoint blockade. Such thermal-responsive engineered bacteria are thus a promising adjuvant therapy to potentiate tumor ablation therapies via effectively activating antitumor immunity.

Lead sulfide colloidal quantum dots (PbS CQDs) show great potential in next-generation photovoltaics. However, their high specific surface area and complex surface crystallography lead to a high surface trap density, which normally requires more than one type of capping ion or ligand to achieve effective surface passivation. In this study, we performed in situ mixed halogen passivation (MHP) during the direct synthesis of semiconducting PbS CQD inks by using different lead halogens. The different halogens can bind with the surface of the CQD throughout the nucleation/growth process, resulting in optimal surface configuration. As a result, the MHP CQD exhibited superior surface passivation compared to the conventionally iodine-capped CQDs. Finally, we achieved a substantial improvement in efficiency from 10.64% to 12.58% after the MHP treatment. Our work demonstrates the advantages of exploring efficient passivation in the directly synthesized CQD inks.

Tumor acidity presents one of the leading causes of tumor immunosuppression (e.g., exhaustion of effector T cells), thereby remarkably attenuating the potency of current immune checkpoint blockade (ICB) therapy in controlling tumor progression. Here, we report that calcium carbonate encapsulated with copolymers of poly (lactic-co-glycolic acid) (PLGA) and PLGA-poly(ethylene glycol) (PLGA-PEG) can work as a proton nano -sponge to neutralize tumor acidity by reacting with protons post intravenous administration. The obtained CaCO3@PLGA NPs can thus promote the reinvigoration of both exhausted CD8+ T cells and innate antitumor immunity. As a result, CaCO3@PLGA NP administration could potentiate the therapeutic efficacies of three ICB therapies toward both CT26 and B16F10 tumor xenografts by preventing exhaustion of CD8+ T cells and acti-vating innate antitumor immunity. Furthermore, we further demonstrate that intratracheal administration of CaCO3@PLGA NPs effectively suppressed lung metastasis of B16F10 melanoma when synergized with systemic anti-PD-1 administration. This work highlights that CaCO3 nanoparticles could be an effective yet safe nano -medicine to generally reinforce ICB therapies toward diverse types of tumors by reversing tumor immunosup-pression, promising for future clinical translation.

Cancer thermal therapy, also known as hyperthermia therapy, has long been exploited to eradicate mass lesions that are now defined as cancer. With the development of corresponding technologies and equipment, local hyperthermia therapies such as radiofrequency ablation, microwave ablation, and high-intensity focused ultrasound, have has been validated to effectively ablate tumors in modern clinical practice. However, they still face many shortcomings, including nonspecific damages to adjacent normal tissues and incomplete ablation particularly for large tumors, restricting their wide clinical usage. Attributed to their versatile physiochemical properties, biomaterials have been specially designed to potentiate local hyperthermia treatments according to their unique working principles. Meanwhile, biomaterial-based delivery systems are able to bridge hyperthermia therapies with other types of treatment strategies such as chemotherapy, radiotherapy and immunotherapy. Therefore, in this review, we discuss recent progress in the development of functional biomaterials to reinforce local hyperthermia by functioning as thermal sensitizers to endow more efficient tumor-localized thermal ablation and/or as delivery vehicles to synergize with other therapeutic modalities for combined cancer treatments. Thereafter, we provide a critical perspective on the further development of biomaterial-assisted local hyperthermia toward clinical applications.

Efferocytosis of apoptotic cancer cells by tumor-associated macrophages or other phagocytes is reported to promote tumor immunosuppression by preventing them from secondary necrosis, which would lead to the release of intracellular components and thus enhanced immunogenicity. Therefore, current apoptosis-inducing cancer treatments (e.g., chemotherapy and radiotherapy) are less satisfactory in eliciting antitumor immunity. Herein, a nanoparticulate inhibitor of efferocytosis is prepared by encapsulating BMS777607, a hydrophobic inhibitor of receptors in macrophages responsible for phosphatidylserine-dependent efferocytosis, with biocompatible poly(lactic-co-glycolic acid) and its amphiphilic derivatives. The yielded nano-BMS can inhibit the efferocytosis of apoptotic cancer cells, thus redirecting them to immunogenic secondary necrosis. As a result, intratumorally injected nano-BMS is capable of activating both innate and adaptive antitumor immunity to achieve greatly improved therapeutic responses, when synergized with nonimmunogenic chemotherapy by cisplatin, immunogenic chemotherapy by oxaliplatin, or radiotherapy by external beams. Moreover, we further demonstrate that the inhalation of nano-BMS could significantly promote the efficacy of cisplatin chemotherapy to suppress tumor lung metastases. Therefore, this study highlights a general strategy to potentiate the immunogenicity of different cancer treatments by suppressing efferocytosis-propelled tumor immunosuppression, showing tremendous clinical potential in rescuing existing cancer therapies for more effective treatment.

The limited penetration depth of external excitation light would remarkably impair the therapeutic efficacy of photodynamic therapy (PDT) and its clinical utilization. Herein, we engineered bioluminescent bacteria by transforming attenuated Salmonella typhimurium strain ΔppGpp (S.T.ΔppGpp) with firefly-luciferase-expressing plasmid (Luc-S.T.ΔppGpp) as an internal light source to evenly illuminate whole tumors. Upon being fixed inside tumors with in-situ formed hydrogel, the colonized Luc-S.T.ΔppGpp together with D-luciferin could continuously generate light to excite photosensitizer chlorin e6 (Ce6), leading to effective suppression of different types of tumors including opaque melanoma and large rabbit tumors. Such bioluminescence-triggered PDT presented significant advantages over conventional PDT excited with an external 660-nm light, which at a much high light energy could only slightly retard the growth of small subcutaneous tumors. Furthermore, we uncovered that Luc-S.T.ΔppGpp boosted PDT could also elicit potent antitumor immunity post the treatment to inhibit tumor metastasis and prevent tumor challenge. Therefore, this work highlights that such bioluminescent bacteria boosted PDT is a general and highly effective therapeutic approach toward diverse cancers with varying light-absorbing capacities and tumor sizes, promising for potential clinical translation because of their acceptable safety profiles.

Microwave ablation (MWA) as a local tumor ablation strategy suffers from posttreatment tumor recurrence. Development of adjuvant biomaterials to potentiate MWA is therefore of practical significance. Here, the high concentration of Ca-2+ fixed by alginate as Ca2+-surplus alginate hydrogel shows enhanced heating efficiency and restricted heating zone under microwave exposure. The high concentration of extracellular Ca2+ synergizes with mild hyperthermia to induce immunogenic cell death by disrupting intracellular Ca2+ homeostasis. Resultantly, Ca2+-surplus alginate hydrogel plus MWA can ablate different tumors on both mice and rabbits at reduced operation powers. This treatment can also elicit antitumor immunity, especially if synergized with Mn2+, an activator of the stimulation of interferon genes pathway, to suppress the growth of both untreated distant tumors and rechallenged tumors. This work highlights that in situ-formed metallo-alginate hydrogel could act as microwave-susceptible and immunostimulatory biomaterial to reinforce the MWA therapy, promising for clinical translation.