Checkpoint blockade immunotherapy is promising for clinical treatment of various malignant tumors. However, checkpoint blockade immunotherapy suffers from a low response rate due to insufficient tumor immunogenicity and the immunosuppressive tumor microenvironment (ITM). In this study, a tumor-microenvironment-activatable binary cooperative prodrug nanoparticle (BCPN) is rationally designed to improve immunotherapy by synergistically modulating the immune tumor microenvironment. BCPN is purely constructed from a tumor acidity and reduction dual-responsive oxaliplatin (OXA) prodrug for triggering immunogenic cell death (ICD) and eliciting antitumor immunity, and a reduction-activatable homodimer of NLG919 for inactivating indoleamine 2,3-dioxygenase 1, which is a key regulator for ITM. Upon tumor-acidity-triggered cleavage of the poly(ethylene glycol) shell, PN shows negative to positive charge switch for enhanced tumor accumulation and deep penetration. OXA and NLG919 are then activated in the tumor cells via glutathione-mediated reduction. It is demonstrate that activated OXA promotes intratumoral accumulation of cytotoxic T lymphocytes by triggering ICD of cancer cells. Meanwhile, NLG919 downregulates IDO-1-mediated immunosuppression and suppresses regulatory T cells. Most importantly, PN shows much higher efficiency than free OXA or the combination of free OXA and NLG919 to regress tumor growth and prevent metastasis of mouse models of both breast and colorectal cancer.

Chemoimmunotherapy by systemic administration of individual regimens suffers from inconsistent pharmacokinetics profiles, low tumor specificity, and severe side effects. Despite promising nanoparticle‐based codelivery approaches in therapeutics, the pathophysiological barriers of solid tumors are a hurdle for tumor accumulation and deep penetration of the drug‐loaded nanoparticles. A light‐inducible nanocargo (LINC) for immunotherapy is reported. LINC is composed of a reduction‐responsive heterodimer of photosensitizer pheophorbide A (PPa) and indoleamine 2,3‐dioxygenase 1 (IDO‐1) inhibitor, i.e., NLG919, and a light‐activatable prodrug of oxaliplatin (OXA). LINC administrated through intravenous injection is passively accumulated at the tumor site to generate near‐infrared (NIR) fluorescence signal. Under fluorescence imaging guidance, the first‐wave of NIR laser irradiation induce reactive oxygen species (ROS) generation, trigger cleavage of the polyethylene glycol (PEG) corona, and thus promote tumor retention and deep penetration of LINC. When exposed to the second‐wave NIR laser illumination, LINC efficiently elicits the immune response and promotes intratumoral infiltration of cytotoxic T lymphocytes (CTLs). Furthermore, NLG919 delivered by LINC reverses the immunosuppressive tumor microenvironment by suppressing IDO‐1 activity. Chemoimmunotherapy with LINC inhibit the tumor growth, lung metastasis, and tumor recurrence. The light‐inducible self‐amplification strategy for improved drug delivery and immunotherapy shows potential.

Immunological tolerance of tumors is characterized by insufficient infiltration of cytotoxic T lymphocytes (CTLs) and immunosuppressive microenvironment of tumor. Tumor resistance to immune checkpoint inhibitors due to immunological tolerance is an ongoing challenge for current immune checkpoint blockade (ICB) therapy. Here, we report the development of tumor microenvironment–activatable anti-PDL1 antibody (αPDL1) nanoparticles for combination immunotherapy designed to overcome immunological tolerance of tumors. Combination of αPDL1 nanoparticle treatment with near-infrared (NIR) laser irradiation–triggered activation of photosensitizer indocyanine green induces the generation of reactive oxygen species, which promotes the intratumoral infiltration of CTLs and sensitizes the tumors to PDL1 blockade therapy. We showed that the combination of antibody nanoparticles and NIR laser irradiation effectively suppressed tumor growth and metastasis to the lung and lymph nodes in mouse models. The nanoplatform that uses the antibody nanoparticle alone both for immune stimulation and PDL1 inhibition could be readily adapted to other immune checkpoint inhibitors for improved ICB therapy.

Photodynamic therapy (PDT) capable of eliciting a robust antitumor immune response has been considered an attractive therapeutic approach. However, adaptive immune resistance in PDT underlines the need to develop alternative strategies. The exquisite power of checkpoint blockade can be harnessed to reinvigorate antitumor immune response. Here, we demonstrate that PDT-triggered adaptive immune resistance can be overcome by inactivating indoleamine 2,3-dioxygenase 1 (IDO-1). We rationally designed a tumor-microenvironment-sheddable prodrug vesicle by integrating a PEGylated photosensitizer (PS) and a reduction-sensitive prodrug of IDO-1 inhibitor. The prodrug vesicles were inert during the blood circulation, whereas they specifically accumulated and penetrated at the tumor site through matrix metalloproteinase-2 (MMP-2)-mediated cleavage of the PEG corona to achieve fluorescence-imaging-guided photodynamic therapy (PDT). Compared to PDT alone, the prodrug-vesicle-mediated combination immunotherapy provoked augmented antitumor immunity to eradicate the tumor in both CT26 colorectal and 4T1 breast immunocompetent mouse models. The prodrug vesicles dramatically suppressed tumor reoccurrence, particularly in overexpressing IDO-1 tumor models, i.e., CT26. This study might provide novel insight into the development of new nanomedicine to enhance the efficacy of photodynamic immunotherapy while addressing the adaptive immune resistance.

Immunotherapy shows promising therapeutic potential for long‐term tumor regression. However, current cancer immunotherapy displays a low response rate due to insufficient immunogenicity of the tumor cells. To address these challenges, herein, intracellular‐acidity‐activatable dynamic nanoparticles for eliciting immunogenicity by inducing ferroptosis of the tumor cells are engineered. The nanoparticles are engineered by integrating an ionizable block copolymer and acid‐liable phenylboronate ester (PBE) dynamic covalent bonds for tumor‐specific delivery of the ferroptosis inducer, a glutathione peroxidase 4 inhibitor RSL‐3. The nanoparticles can stably encapsulate RSL‐3 inside the hydrophobic core via π–π stacking interaction with the PBE groups at neutral pH (pH = 7.4), while releasing the payload in the endocytic vesicles (pH = 5.8–6.2) by acidity‐triggered cleavage of the PBE dynamic covalent bonds. Furthermore, the nanoparticles can perform acid‐activatable photodynamic therapy by protonation of the ionizable core, and significantly recruit tumor‐infiltrating T lymphocytes for interferon gamma secretion, and thus sensitize the tumor cells to RSL‐3‐inducible ferroptosis. The combination of nanoparticle‐induced ferroptosis and blockade of programmed death ligand 1 efficiently inhibits growth of B16‐F10 melanoma tumor and lung metastasis of 4T1 breast tumors, suggesting the promising potential of ferroptosis induction for promoting cancer immunotherapy.

Combination cancer immunotherapy has shown promising potential for simultaneously eliciting antitumor immunity and modulating the immunosuppressive tumor microenvironment (ITM). However, combination immunotherapy with multiple regimens suffers from the varied chemophysical properties and inconsistent pharmacokinetic profiles of the different therapeutics. To achieve tumor-specific codelivery of the immune modulators, an indocyanine green (ICG)-templated self-assembly strategy for preparing dual drug-loaded two-in-one nanomedicine is reported. ICG-templated self-assembly of paclitaxel (PTX) nanoparticles (ISPN), and the application of ISPN for combination immunotherapy of the triple negative breast cancer (TNBC) are demonstrated. The ISPN show satisfied colloidal stability and high efficacy for tumor-specific codelivery of ICG and PTX through the enhanced tumor permeability and retention effect. Upon laser irradiation, the ICG component of ISPN highly efficiently induces immunogenic cell death of the tumor cells via activating antitumor immune response through photodynamic therapy. Meanwhile, PTX delivered by ISPN suppresses the regulatory T lymphocytes (T regs ) to combat ITM. The combination treatment of TNBCwith ISPN and αPD-L1-medaited immune checkpoint blockade therapy displays a synergistic effect on tumor regression, metastasis inhibition, and recurrence prevention. Overall, the ICG-templated nanomedicine may represent a robust nanoplatform for combination immunotherapy.

Neoantigen-based cancer vaccines are promising for boosting cytotoxic T lymphocyte (CTL) responses. However, the therapeutic effect of cancer vaccines is severely blunted by functional suppression of the dendritic cells (DCs). Herein, we demonstrated an acid-responsive polymeric nanovaccine for activating the stimulator of interferon genes (STING) pathway and improving cancer immunotherapy. The nanovaccines were fabricated by integrating an acid-activatable polymeric conjugate of the STING agonist and neoantigen into one single nanoplatform. The nanovaccines efficiently accumulated at the lymph nodes for promoting DC uptake and facilitating cytosol release of the neoantigens. Meanwhile, the STING agonist activated the STING pathway in the DCs to elicit interferon-β secretion and to boost T-cell priming with the neoantigen. The nanovaccine dramatically inhibited tumor growth and occurrence of B16-OVA melanoma and 4T1 breast tumors in immunocompetent mouse models. Combination immunotherapy with the nanovaccines and anti-PD-L1 antibody demonstrated further improved antitumor efficacy in a 4T1 breast tumor model.

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