Nanotherapeutics: Tumor and intratumoral pathogen cascade-targeting photothermal nanotherapeutics for boosted immunotherapy of colorectal cancer

Journal of Controlled Release Volume 379 , 10 March 2025 , Pages 574-591 Volume 379 , 10 March 2025 , Pages 574-591 Author links open overlay panel Youtao Xin a , Yunjian Yu a , Mengdi Wu a , Meihui Su a , Mahmoud Elsabahy b , Xiongwei Qu c , Hui Gao a Author links open overlay panel Youtao Xin a , Yunjian Yu a , Mengdi Wu a , Meihui Su a , Mahmoud Elsabahy b , Xiongwei Qu c , Hui Gao a Author links open overlay panel Youtao Xin a , Yunjian Yu a , Mengdi Wu a , Meihui Su a , Mahmoud Elsabahy b , Xiongwei Qu c , Hui Gao a Add to Mendeley Share Cite Share Share Share Cite Cite Cite Abstract Clinical benefits of immunotherapy in colorectal cancer (CRC) are limited due to the low immunogenicity and immunosuppressive tumor microenvironment. Fusobacterium nucleatum ( Fn ) is discovered to colonize CRC tumors and dampen immunotherapy by fostering an immunosuppressive TME. Herein, a controllable "Shielding-deshielding" N -acetylgalactosamine (GalNAc)-derived photothermal nanotherapeutic is developed to mediate cascade targeting toward tumor and intratumoral Fn for enhanced photothermal-immunotherapy. This nanotherapeutic can in situ generate near infrared-II laser-activatable photothermal agent by reacting with endogenous hydrogen sulfide in CRC. The Schiff bond-tethered hyaluronic acid coating not only facilitates precise localization within CRC but shieldes GalNAc-mediated liver targeting, which can be deshielded upon a slightly acidic TME to anchor Fn by binding to its lectin Fap2. This cascade-targeting nanotherapeutic enables efficacious tumor accumulation and reinforces photothermal therapy (PTT) efficacy. Notably, PTT efficiently induces immunogenic cell death in CRC cells, leading to augmented immunogenicity and CD8 + T cell activation. Meanwhile, synchronous eradication of Fn facilitates M1 macrophage polarization, and promotes intratumoral infiltration of CD8 + T cell by reducing succinic acid level, thereby further boosting antitumor immunity against both primary and distant tumors. Overall, this study involving cascade targeting-reinforced PTT and intratumoral microorganism modulation offers new insight into effective CRC immunotherapy. Graphical abstract A cascade-targeting photothermal nanotherapeutic toward tumor and intratumoral Fn was fabricated to reinforce photothermal-immunotherapy of CRC by synchronously ameliorating immunogenicity and reversing immunosuppressive TME. Download: Download high-res image (89KB) Download: Download full-size image Abstract Clinical benefits of immunotherapy in colorectal cancer (CRC) are limited due to the low immunogenicity and immunosuppressive tumor microenvironment. Fusobacterium nucleatum ( Fn ) is discovered to colonize CRC tumors and dampen immunotherapy by fostering an immunosuppressive TME. Herein, a controllable "Shielding-deshielding" N -acetylgalactosamine (GalNAc)-derived photothermal nanotherapeutic is developed to mediate cascade targeting toward tumor and intratumoral Fn for enhanced photothermal-immunotherapy. This nanotherapeutic can in situ generate near infrared-II laser-activatable photothermal agent by reacting with endogenous hydrogen sulfide in CRC. The Schiff bond-tethered hyaluronic acid coating not only facilitates precise localization within CRC but shieldes GalNAc-mediated liver targeting, which can be deshielded upon a slightly acidic TME to anchor Fn by binding to its lectin Fap2. This cascade-targeting nanotherapeutic enables efficacious tumor accumulation and reinforces photothermal therapy (PTT) efficacy. Notably, PTT efficiently induces immunogenic cell death in CRC cells, leading to augmented immunogenicity and CD8 + T cell activation. Meanwhile, synchronous eradication of Fn facilitates M1 macrophage polarization, and promotes intratumoral infiltration of CD8 + T cell by reducing succinic acid level, thereby further boosting antitumor immunity against both primary and distant tumors. Overall, this study involving cascade targeting-reinforced PTT and intratumoral microorganism modulation offers new insight into effective CRC immunotherapy. Abstract Clinical benefits of immunotherapy in colorectal cancer (CRC) are limited due to the low immunogenicity and immunosuppressive tumor microenvironment. Fusobacterium nucleatum ( Fn ) is discovered to colonize CRC tumors and dampen immunotherapy by fostering an immunosuppressive TME. Herein, a controllable "Shielding-deshielding" N -acetylgalactosamine (GalNAc)-derived photothermal nanotherapeutic is developed to mediate cascade targeting toward tumor and intratumoral Fn for enhanced photothermal-immunotherapy. This nanotherapeutic can in situ generate near infrared-II laser-activatable photothermal agent by reacting with endogenous hydrogen sulfide in CRC. The Schiff bond-tethered hyaluronic acid coating not only facilitates precise localization within CRC but shieldes GalNAc-mediated liver targeting, which can be deshielded upon a slightly acidic TME to anchor Fn by binding to its lectin Fap2. This cascade-targeting nanotherapeutic enables efficacious tumor accumulation and reinforces photothermal therapy (PTT) efficacy. Notably, PTT efficiently induces immunogenic cell death in CRC cells, leading to augmented immunogenicity and CD8 + T cell activation. Meanwhile, synchronous eradication of Fn facilitates M1 macrophage polarization, and promotes intratumoral infiltration of CD8 + T cell by reducing succinic acid level, thereby further boosting antitumor immunity against both primary and distant tumors. Overall, this study involving cascade targeting-reinforced PTT and intratumoral microorganism modulation offers new insight into effective CRC immunotherapy. Clinical benefits of immunotherapy in colorectal cancer (CRC) are limited due to the low immunogenicity and immunosuppressive tumor microenvironment. Fusobacterium nucleatum ( Fn ) is discovered to colonize CRC tumors and dampen immunotherapy by fostering an immunosuppressive TME. Herein, a controllable "Shielding-deshielding" N -acetylgalactosamine (GalNAc)-derived photothermal nanotherapeutic is developed to mediate cascade targeting toward tumor and intratumoral Fn for enhanced photothermal-immunotherapy. This nanotherapeutic can in situ generate near infrared-II laser-activatable photothermal agent by reacting with endogenous hydrogen sulfide in CRC. The Schiff bond-tethered hyaluronic acid coating not only facilitates precise localization within CRC but shieldes GalNAc-mediated liver targeting, which can be deshielded upon a slightly acidic TME to anchor Fn by binding to its lectin Fap2. This cascade-targeting nanotherapeutic enables efficacious tumor accumulation and reinforces photothermal therapy (PTT) efficacy. Notably, PTT efficiently induces immunogenic cell death in CRC cells, leading to augmented immunogenicity and CD8 + T cell activation. Meanwhile, synchronous eradication of Fn facilitates M1 macrophage polarization, and promotes intratumoral infiltration of CD8 + T cell by reducing succinic acid level, thereby further boosting antitumor immunity against both primary and distant tumors. Overall, this study involving cascade targeting-reinforced PTT and intratumoral microorganism modulation offers new insight into effective CRC immunotherapy. Graphical abstract A cascade-targeting photothermal nanotherapeutic toward tumor and intratumoral Fn was fabricated to reinforce photothermal-immunotherapy of CRC by synchronously ameliorating immunogenicity and reversing immunosuppressive TME. Download: Download high-res image (89KB) Download: Download full-size image Graphical abstract A cascade-targeting photothermal nanotherapeutic toward tumor and intratumoral Fn was fabricated to reinforce photothermal-immunotherapy of CRC by synchronously ameliorating immunogenicity and reversing immunosuppressive TME. Download: Download high-res image (89KB) Download: Download full-size image A cascade-targeting photothermal nanotherapeutic toward tumor and intratumoral Fn was fabricated to reinforce photothermal-immunotherapy of CRC by synchronously ameliorating immunogenicity and reversing immunosuppressive TME. Download: Download high-res image (89KB) Download: Download full-size image Introduction Colorectal cancer (CRC) represents the third most diagnosed cancer and the second leading cause of cancer deaths worldwide [1]. Despite advances in early screening techniques, approximately 25% of CRC patients are diagnosed at stage 4, while 25%-50% of individuals initially diagnosed with early-stage disease progress to develop metastatic disease in developed countries [[2], [3], [4]]. The effectiveness of surgery and adjuvant chemotherapy in treating patients with advanced or metastatic CRC remains low, with a median 5-year survival rate of only 12.5% in the United States [5], highlighting the urgent need for more effective treatment options for CRC patients. As a burgeoning therapeutic approach, cancer immunotherapy has recently achieved remarkable success by generating long-term durable responses in solid tumors that were previously challenging to treat [6]. Especially, immune checkpoint blockade (ICB) therapy has proved its robust effectiveness in various cancer types, such as lung cancer, melanoma, and lymphoma [7]. Unfortunately, approximately 95% of CRC patients benefited little from ICB therapy due to the low tumor immunogenicity and the lack of immune cell infiltration [[8], [9], [10]]. Therefore, there is a strong demand for alternative high-performance modalities that target the modulation of the tumor microenvironment (TME) to enhance CRC immunotherapy and advance patient outcomes. As a non-invasive therapeutic manner that leverages hyperthermia for cell ablation, photothermal therapy (PTT) has recently appealed enormous attentions for its potency in suppressing primary tumors as well as improving tumor immunogenicity to further elicit robust immune responses for distant tumors [11,12]. PTT-induced immunogenic cell death (ICD) trigger