Shi-Ying Li

Conventional cancer therapies rarely induce robust antitumor immunity, as they typically trigger non‐immunogenic cell death and fail to counteract intrinsic immune resistance mechanisms. In this work, we develop a charged multivesicular body protein 2B (CHMP2B)‐targeting photodynamic degrader (Chat‐PDD) that both activates and amplifies pyroptosis‐mediated antitumor immunity. Chat‐PDD is assembled from a CHMP2B‐targeting chimeric peptide (Chat‐CHP), composed of a CHMP2B‐binding sequence, the photosensitizer protoporphyrin IX (PpIX), and a membrane‐anchoring palmitic acid moiety, and is co‐formulated with the glycogen synthase kinase‐3 (GSK‐3) inhibitor elraglusib (Elr). Chat‐PDD selectively accumulates on tumor cell membranes and localizes to CHMP2B. Upon photoactivation, membrane‐confined photodynamic therapy disrupts the plasma membrane, facilitates CHMP2B degradation, and directly triggers pyroptotic cell death. Concurrently, GSK‐3 inhibition enhances granzyme B secretion to potentiate T cell cytotoxicity. Notably, photodynamic degradation of CHMP2B impairs endosomal sorting complex required for transport III (ESCRT‐III)‐dependent membrane repair, thereby amplifying the release of damage‐associated molecular pattern (DAMP) and reinforcing granzyme B‐mediated killing. By inducing pyroptosis and blocking the membrane repair pathway, Chat‐PDD elicits systemic antitumor immunity and effectively suppresses metastatic progression. This work presents a sophisticated strategy to reprogram tumor cell death pathways and overcome their inherent resistance to immune activation.

The effectiveness of immunotherapy is significantly limited by the inherently low immunogenicity and immunosuppressive phenotypes of tumors. To address this challenge, we develop assemblies composed of chlorin e6 and regorafenib (designated as CeRe), which combine photodynamic therapy (PDT) with immune regulatiing functions. CeRe exhibits uniform nanoscale distribution and good stability without requiring additional carriers. Upon light activation, CeRe eradicate tumor cells via PDT-induced reactive oxygen species (ROS) while simultaneously triggering immunogenic cell death (ICD). Furthermore, CeRe downregulates PD-L1 expression in tumor cells, promotes macrophage polarization, and relieves the immunosuppressive tumor microenvironment (TME). These synergistic immunomodulatory effects substantially improve tumor responsiveness to αPD-L1 treatment, leading to the effective inhibition of both primary and metastatic tumor growth. Collectively, this work presents a carrier-free nanodrug assembly strategy with multifaceted mechanisms, offering a promising approach for precise tumor therapy and metastasis suppression.

Prostate-specific membrane antigen (PSMA)-targeting peptide–drug conjugates (PDCs) offer promise for the treatment of PSMA-positive prostate cancer, but their applications are limited by rapid clearance, poor pharmacokinetics, and low efficacy. Herein, we design a series of PDCs incorporating rational functional moieties, including a Glu–Ureido–Lys PSMA-targeting ligand, the cytotoxic payload monomethyl auristatin E (MMAE), and a cathepsin B-cleavable Val–Cit linker, combined with structural modifications such as free amine exposure, acetylation, stearic acid acylation, or p-iodophenylbutyric acid (PIBA) conjugation. Among them, the stearic acid-modified PSMA-targeting PDC (PDC-C18) is identified as a long-acting candidate for treating prostate cancer. PDC-C18 rapidly forms stable nanocomplexes with human serum albumin (HSA) through hydrophobic interactions, effectively shielding its hydrophobic moiety while preserving PSMA specificity. Notably, PDC-C18 exhibits a more than 160-fold extension in half-life compared to conventional PDCs, prolongs mean residence time (MRT) from 12.47 h to 23.93 h relative to PIBA-modified PDCs, and achieves a 60-fold reduction in clearance rate. This long-acting property translates into a remarkable tumor suppression rate of 96.91%, simultaneously avoiding the side effects associated with traditional PIBA modification strategies. Overall, this study presents an effective approach to improving the pharmacokinetic behavior of PDCs and provides valuable insights for the development of next-generation tumor-targeted therapies.

The inherently low immunogenicity and immune evasion properties of breast cancer cells present major obstacles to the effective activation of antitumor immune responses. To overcome these challenges, we develop a Golgi apparatus‐targeting immunostimulant (GA‐IS) that synergistically enhances antitumor immunity through the induction of pyroptosis and degradation of PD‐L1. GA‐IS is based on an amphiphilic chimeric peptide (GA‐Chip), which consists of a Golgi apparatus‐targeting sequence (SDYQRL), a hydrophobic palmitic acid moiety, and the photosensitizer protoporphyrin IX (PpIX). This construct is co‐formulated with the PD‐L1 degrader dBET57 using DSPE‐PEG ₂₀₀₀ to improve stability and systemic delivery. Upon accumulation in tumor cells, GA‐IS enables precise drug delivery to the Golgi apparatus and elicits localized photodynamic effects, thereby inducing pyroptotic cell death and robust immunogenic cell death (ICD), ultimately enhancing tumor immunogenicity. Critically, GA‐IS also downregulates PD‐L1 expression via BRD4 degradation, effectively disrupting immune checkpoint signaling and restoring immune surveillance. As a result, GA‐IS elicits a potent systemic immune response capable of suppressing both primary and metastatic breast cancer, while showing minimal systemic toxicity. This Golgi apparatus‐targeting immunostimulant represents a promising strategy to reverse immune suppression in breast cancer and advance precision immunotherapy.

Epigenetic abnormalities play a pivotal role in tumorigenesis, serving as a driving force independent of genetic mutations. Over the past decade, substantial progress has been made in identifying key epigenetic targets, leading to the development of numerous epigenetic drugs. Notably, these agents extend beyond direct tumor suppression by actively modulating the tumor microenvironment, particularly shaping immune cell function. This dual effect of epigenetic drugs, targeting either cancer cells or immune cells to modulate their crosstalk, holds great promise for enhancing antitumor immunity in combination with immunotherapies. Moreover, integrating epigenetic drugs into advanced drug delivery systems enhances their bioavailability and therapeutic index, maximizing their potential while minimizing toxicity for clinical translation. This review examines the intricate interplay between epigenetic modifications and cancer progression, highlights key epigenetic reprogramming biomedicines, and explores their synergistic potential in enhancing immunotherapeutic efficacy.

Lymphatic metastasis is a major cause of tumor treatment failure, with the immunosuppressive status of lymphatic macrophages significantly impairing antitumor immunity. In this study, it is found that CD169 ⁺ macrophages in lymphatic metastasis exhibit impaired phagocytic activity and diminished antigen‐presenting capacity, which correlates with suppressed antitumor immune responses. Based on these discoveries, a CD169 ⁺ macrophage‐targeted immunomodulator (designated as G‐LNP@S‐D) is fabricated to restore phagocytic function and enhance antigen presentation for lymphatic metastasis eradication. G‐LNP@S‐D consists of GM1‐functionalized liposomes co‐encapsulating the SHP2 inhibitor SHP099 and the STING agonist DMXAA, enabling sequential lymph node‐ and CD169 ⁺ macrophage‐specific drug delivery. Mechanistically, G‐LNP@S‐D not only restores the phagocytic capacity of CD169 ⁺ macrophages to eliminate tumor cells but also activates the STING pathway to enhance antigen presentation and subsequent T cell priming. Immunological profiling confirms that G‐LNP@S‐D treatment promotes the infiltration of CD4 ⁺ and CD8 ⁺ T cells in both TDLNs and primary tumors. Importantly, G‐LNP@S‐D exerts systemic immunomodulatory effects for directly eradicating lymphatic metastases. This study elucidates a sophisticated lymph node immune‐modulation strategy and provides a promising therapeutic approach to treat lymphatic metastasis.