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.

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.