Self-sufficient nanoparticles with dual-enzyme activity trigger radical storms and activate cascade-amplified antitumor immunologic responses.

Radiotherapy (RT) can potentially induce systemic immune responses by initiating immunogenic cell death (ICD) of tumor cells. However, RT-induced antitumor immunologic responses are sporadic and insufficient against cancer metastases. Herein, we construct multifunctional self-sufficient nanoparticles (MARS) with dual-enzyme activity (GOx and peroxidase-like) to trigger radical storms and activate the cascade-amplified systemic immune responses to suppress both local tumors and metastatic relapse. In addition to limiting the Warburg effect to actualize starvation therapy, MARS catalyzes glucose to produce hydrogen peroxide (H2O2), which is then used in the Cu+-mediated Fenton-like reaction and RT sensitization. RT and chemodynamic therapy produce reactive oxygen species in the form of radical storms, which have a robust ICD impact on mobilizing the immune system. Thus, when MARS is combined with RT, potent systemic antitumor immunity can be generated by activating antigen-presenting cells, promoting dendritic cells maturation, increasing the infiltration of cytotoxic T lymphocytes, and reprogramming the immunosuppressive tumor microenvironment. Furthermore, the synergistic therapy of RT and MARS effectively suppresses local tumor growth, increases mouse longevity, and results in a 90% reduction in lung metastasis and postoperative recurrence. Overall, we provide a viable approach to treating cancer by inducing radical storms and activating cascade-amplified systemic immunity.

Reversing cancer immunoediting phases with a tumor-activated and optically reinforced immunoscaffold.

In situ vaccine (ISV) is a promising immunotherapeutic tactic due to its complete tumoral antigenic repertoire. However, its efficiency is limited by extrinsic inevitable immunosuppression and intrinsic immunogenicity scarcity. To break this plight, a tumor-activated and optically reinforced immunoscaffold (TURN) is exploited to trigger cancer immunoediting phases regression, thus levering potent systemic antitumor immune responses. Upon response to tumoral reactive oxygen species, TURN will first release RGX-104 to attenuate excessive immunosuppressive cells and cytokines, and thus immunosuppression falls and immunogenicity rises. Subsequently, intermittent laser irradiation-activated photothermal agents (PL) trigger abundant tumor antigens exposure, which causes immunogenicity springs and preliminary infiltration of T cells. Finally, CD137 agonists from TURN further promotes the proliferation, function, and survival of T cells for durable antitumor effects. Therefore, cancer immunoediting phases reverse and systemic antitumor immune responses occur. TURN achieves over 90 % tumor growth inhibition in both primary and secondary tumor lesions, induces potent systemic immune responses, and triggers superior long-term immune memory in vivo. Taken together, TURN provides a prospective sight for ISV from the perspective of immunoediting phases.

Breaking the Tumor Chronic Inflammation Balance with a Programmable Release and Multi-Stimulation Engineering Scaffold for Potent Immunotherapy.

Tumor-associated chronic inflammation severely restricts the efficacy of immunotherapy in cold tumors. Here, a programmable release hydrogel-based engineering scaffold with multi-stimulation and reactive oxygen species (ROS)-response (PHOENIX) is demonstrated to break the chronic inflammatory balance in cold tumors to induce potent immunity. PHOENIX can undergo programmable release of resiquimod and anti-OX40 under ROS. Resiquimod is first released, leading to antigen-presenting cell maturation and the transformation of myeloid-derived suppressor cells and M2 macrophages into an antitumor immune phenotype. Subsequently, anti-OX40 is transported into the tumor microenvironment, leading to effector T-cell activation and inhibition of Treg function. PHOENIX consequently breaks the chronic inflammation in the tumor microenvironment and leads to a potent immune response. In mice bearing subcutaneous triple-negative breast cancer and metastasis models, PHOENIX effectively inhibited 80% and 60% of tumor growth, respectively. Moreover, PHOENIX protected 100% of the mice against TNBC tumor rechallenge by electing a robust long-term antigen-specific immune response. An excellent inhibition and prolonged survival in PHOENIX-treated mice with colorectal cancer and melanoma is also observed. This work presents a potent therapeutic scaffold to improve immunotherapy efficiency, representing a generalizable and facile regimen for cold tumors.

A Multivalent Personalized Vaccine Orchestrating Two-Signal Activation Rebuilds the Bridge Between Innate and Adaptive Antitumor Immunity.

Personalized vaccines capable of circumventing tumor heterogeneity have exhibited compelling prospects. However, their therapeutic benefit is greatly hindered by the limited antigen repertoire and poor response of CD8+ T-cell immunity. Here, a double-signal coregulated cross-linking hydrogel-based vaccine (Bridge-Vax) is engineered to rebuild the bridge between innate and adaptive immunity for activating CD8+ T-cells against full repertoire of tumor antigens. Mechanistically, unlike prominent CD4+ T-cell responses in most cases, administration of Bridge-Vax encapsulated with granulocyte-macrophage colony-stimulating factor concentrates a wave of dendritic cells (DCs), which further promotes DCs activation with costimulatory signal by the self-adjuvanted nature of polysaccharide hydrogel. Simultaneously, synergy with the increased MHC-I epitopes by codelivered simvastatin for cross-presentation enhancement, Bridge-Vax endows DCs with necessary two signals for orchestrating CD8+ T-cell activation. Bridge-Vax elicits potent antigen-specific CD8+ T-cell responses in vivo, which not only shows efficacy in B16-OVA model but confers specific immunological memory to protect against tumor rechallenge. Moreover, personalized multivalent Bridge-Vax tailored by leveraging autologous tumor cell membranes as antigens inhibits postsurgical B16F10 tumor recurrence. Hence, this work provides a facile strategy to rebuild the bridge between innate and adaptive immunity for inducing potent CD8+ T-cell immunity and would be a powerful tool for personalized cancer immunotherapy.

Antigenicity and adjuvanticity co-reinforced personalized cell vaccines based on self-adjuvanted hydrogel for post-surgical cancer vaccination.

Cancer vaccine-based postsurgical immunotherapy is emerging as a promising approach in patients following surgical resection for inhibition of tumor recurrence. However, low immunogenicity and insufficient cancer antigens limit the widespread application of postoperative cancer vaccines. Here, we propose a "trash to treasure" cancer vaccine strategy to enhance postsurgical personalized immunotherapy, in which antigenicity and adjuvanticity of purified surgically exfoliated autologous tumors (with whole antigen repertoire) were co-reinforced. In the antigenicity and adjuvanticity co-reinforced personalized vaccine (Angel-Vax), polyriboinosinic: polyribocytidylic acid (pIC) and tumor cells that have undergone immunogenic death are encapsulated in a self-adjuvanted hydrogel formed by cross-linking of mannan and polyethyleneimine. Angel-Vax exhibits an enhanced capacity on antigen-presenting cells stimulation and maturation compared to its individual components in vitro. Immunization with Angel-Vax provokes an efficient systemic cytotoxic T-cell immune response, contributing to the satisfied prophylactic and therapeutic efficacy in mice. Furthermore, when combined with immune checkpoint inhibitors (ICI), Angel-Vax effectively prevented postsurgical tumor recurrence, as evidenced by an increase in median survival of approximately 35% compared with ICI alone. Unlike the cumbersome preparation process of postoperative cancer vaccines, the simple and feasible approach herein may represent a general strategy for various kinds of tumor cell-based antigens in the inhibition of postsurgical tumor relapse by reinforced immunogenicity.

A tactical nanomissile mobilizing antitumor immunity enables neoadjuvant chemo-immunotherapy to minimize postsurgical tumor metastasis and recurrence.

Neoadjuvant chemotherapy has become an indispensable weapon against high-risk resectable cancers, which benefits from tumor downstaging. However, the utility of chemotherapeutics alone as a neoadjuvant agent is incapable of generating durable therapeutic benefits to prevent postsurgical tumor metastasis and recurrence. Herein, a tactical nanomissile (TALE), equipped with a guidance system (PD-L1 monoclonal antibody), ammunition (mitoxantrone, Mit), and projectile bodies (tertiary amines modified azobenzene derivatives), is designed as a neoadjuvant chemo-immunotherapy setting, which aims at targeting tumor cells, and fast-releasing Mit owing to the intracellular azoreductase, thereby inducing immunogenic tumor cells death, and forming an in situ tumor vaccine containing damage-associated molecular patterns and multiple tumor antigen epitopes to mobilize the immune system. The formed in situ tumor vaccine can recruit and activate antigen-presenting cells, and ultimately increase the infiltration of CD8+ T cells while reversing the immunosuppression microenvironment. Moreover, this approach provokes a robust systemic immune response and immunological memory, as evidenced by preventing 83.3% of mice from postsurgical metastasis or recurrence in the B16-F10 tumor mouse model. Collectively, our results highlight the potential of TALE as a neoadjuvant chemo-immunotherapy paradigm that can not only debulk tumors but generate a long-term immunosurveillance to maximize the durable benefits of neoadjuvant chemotherapy.

A cooperative nano-CRISPR scaffold potentiates immunotherapy via activation of tumour-intrinsic pyroptosis.

Efficient cancer immunotherapy depends on selective targeting of high bioactivity therapeutic agents to the tumours. However, delivering exogenous medication might prove difficult in clinical practice. Here we report a cooperative Nano-CRISPR scaffold (Nano-CD) that utilizes a specific sgRNA, selected from a functional screen for triggering endogenous GDSME expression, while releasing cisplatin to initiate immunologic cell death. Mechanistically, cascade-amplification of the antitumor immune response is prompted by the adjuvantic properties of the lytic intracellular content and enhanced by the heightened GDSME expression, resulting in pyroptosis and the release of tumor associated antigens. Neither of the single components provide efficient tumour control, while tumor growth is efficiently inhibited in primary and recurrent melanomas due to the combinatorial effect of cisplatin and self-supplied GSDME. Moreover, Nano-CD in combination with checkpoint blockade creates durable immune memory and strong systemic anti-tumor immune response, leading to disease relapse prevention, lung metastasis inhibition and increased survival in mouse melanomas. Taken together, our therapeutic approach utilizes CRISPR-technology to enable cell-intrinsic protein expression for immunotherapy, using GDSME as prototypic immune modulator. This nanoplatform thus can be applied to modulate further immunological processes for therapeutic benefit.

Tumor Environment Regression Therapy Implemented by Switchable Prune-to-Essence Nanoplatform Unleashed Systemic Immune Responses.

Coevolution of tumor cells and surrounding stroma results in protective protumoral environment, in which abundant vessel, stiff structure and immunosuppression promote each other, cooperatively incurring deterioration and treatment compromise. Reversing suchenvironment may transform tumors from treatment-resistant to treatment-vulnerable. However, effective reversion requires synergistic comprehensive regression of such environment under precise control. Here, the first attempt to collaboratively retrograde coevolutionary tumor environment to pre-oncogenesis status, defined as tumor environment regression therapy, is made for vigorous immune response eruption by a switchable prune-to-essence nanoplatform (Pres) with simplified composition and fabrication process. Through magnetic targeting and multimodal imaging of Pres, tumor environment regression therapy is guided, optimized and accomplished in a trinity way: Antiangiogenesis is executed to rarefy vessels to impede tumor progression. By seizing the time, cancer associated fibroblasts are eliminated to diminish collagen and loosen the stiff structure for deep penetration of Pres, which alternately functioned in deeper tumors, forming a positive feedback loop. Through this loop, immune cell infiltration, immunosuppression mitigation and immunogenic cells death induction are all fulfilled and further escalated in the regressed environment. These transformations consequently unleashed systemic immune responses and generated immune memory against carcinoma. This study provides new insights intotreatment of solid tumors.