Immunotherapy has achieved great success recently and opened a new avenue for anti-tumor treatment. Programmed cell death 1/programmed cell death ligand 1 (PD-1/PD-L1) are typical immune checkpoints that transmit coinhibitory signals, muting the host immunity. Monoclonal antibodies that block PD-1/PD-L1 axis have benefited many patients with different tumor diseases. However, the objective response rate is still unsatisfactory. In this review, we summarize three strategies targeting PD-L1 based on different forms of PD-L1 and various regulating mechanisms to enhance the therapeutic effect, including blockade of the interaction between PD-L1 and PD-1, downregulation of PD-L1 expression and degradation of mature PD-L1. Thereinto, we describe a variety of materials have been designed to target PD-L1, including antibodies, nanoparticle, peptide, aptamer, RNA, and small molecule. Additionally, we list the drugs with PD-L1 regulation capacity used in clinical and ongoing studies to explore other alternatives for targeting PD-L1 besides anti-PD-L1 monoclonal antibodies. Moreover, we discuss associated opportunities for cancer combination therapy with other modalities such as chemotherapy, radiotherapy, photodynamic therapy (PDT) and photothermal therapy (PTT), as these conventional or emerging modalities are capable of increasing the immune response of tumor cells by altering the tumor microenvironment (TME), and would display synergistic effect. At last, we give a brief summary and outlook regarding the research status and future prospect of immunotherapy.

/pdf/strategies-targeting-pd-l1-expression-and-associated-3ubpsj1f.pdf

Strategies targeting PD-L1 expression and associated opportunities for cancer combination therapy

Cytokines are critical in regulating immune responses and cellular behavior, playing dual roles in both normal physiology and the pathology of diseases such as cancer. These molecules, including interleukins, interferons, tumor necrosis factors, chemokines, and growth factors like TGF-β, VEGF, and EGF, can promote or inhibit tumor growth, influence the tumor microenvironment, and impact the efficacy of cancer treatments. Recent advances in targeting these pathways have shown promising therapeutic potential, offering new strategies to modulate the immune system, inhibit tumor progression, and overcome resistance to conventional therapies. In this review, we summarized the current understanding and therapeutic implications of targeting cytokine and chemokine signaling pathways in cancer. By exploring the roles of these molecules in tumor biology and the immune response, we highlighted the development of novel therapeutic agents aimed at modulating these pathways to combat cancer. The review elaborated on the dual nature of cytokines as both promoters and suppressors of tumorigenesis, depending on the context, and discussed the challenges and opportunities this presents for therapeutic intervention. We also examined the latest advancements in targeted therapies, including monoclonal antibodies, bispecific antibodies, receptor inhibitors, fusion proteins, engineered cytokine variants, and their impact on tumor growth, metastasis, and the tumor microenvironment. Additionally, we evaluated the potential of combining these targeted therapies with other treatment modalities to overcome resistance and improve patient outcomes. Besides, we also focused on the ongoing research and clinical trials that are pivotal in advancing our understanding and application of cytokine- and chemokine-targeted therapies for cancer patients. 

Targeting cytokine and chemokine signaling pathways for cancer therapy

The therapeutic application of STING agonists in various malignancies has been limited by factors such as the inability of systemic administration and the immunosuppressive tumor microenvironment. Herein, this work reports a mesoporous polydopamine‐based multifunctional nanoplatform loaded with STING agonist MSA‐2 and chelated with Mn2+ for synergistic photothermal and STING activation‐based immunotherapy. The nanoplatform effectively delivers MSA‐2 to the tumor site and intelligently releases its contents through acid degradation, facilitated by the photothermal effect. Additionally, the thermal ablation of tumor tissue can induce immunogenic cell death, which helps alleviate the immunosuppressive tumor microenvironment, thereby enhancing the efficacy of MSA‐2. Furthermore, Mn2+ works as a dual‐acting STING sensitizer and MRI contrast agent which not only boosts the immune response but also allows real‐time MRI tracking of the nanoplatform. This strategy is proved highly efficacious both in impeding primary/metastatic tumor and in eliciting a robust tumor‐specific immune response. Collectively, an effective multifunctional nanoplatform for the systemic delivery of STING agonist which synergized photothermal therapy and STING pathway activation‐mediated immunotherapy is highlighted here to provide new ideas and strategies for optimizing combination therapy for cancer treatment.

Multifunctional Mesoporous Polydopamine‐Based Systematic Delivery of STING Agonist for Enhanced Synergistic Photothermal‐Immunotherapy

The immunotherapy efficiency of stimulator of interferon genes (STING)-activatable drugs (e.g., 7-ethyl-10-hydroxycamptothecin, SN38) is limited by their non-specificity to tumor cells and the slow excretion of the DNA-containing exosomes from the treated cancer cells. The efficacy of tumor ferroptosis therapy is always limited by the elimination of lipid peroxides (LPO) by the pathways of glutathione peroxidase 4 (GPX4), dihydroorotate dehydrogenase (DHODH) and ferroptosis suppressor protein 1(FSP1). To solve these problems, in this study, we developed a STING pathway-activatable contrast agent (i.e., FeGd-HN@TA-Fe2+-SN38 nanoparticles) for magnetic resonance imaging (MRI)-guided tumor immunoferroptosis synergistic therapy. The remarkable in vivo MRI performance of FeGd-HN@TA-Fe2+-SN38 is attributed to its high accumulation at tumor location, the high relaxivities of FeGd-HN core, and the pH-sensitive TA-Fe2+-SN38 layer. The effectiveness and biosafety of the immunoferroptosis synergistic therapy induced by FeGd-HN@TA-Fe2+-SN38 are demonstrated by the in vivo investigations on the 4T1 tumor-bearing mice. The mechanisms of in vivo immunoferroptosis synergistic therapy by FeGd-HN@TA-Fe2+-SN38 are demonstrated by measurements of in vivo ROS, LPO, GPX4 and SLC7A11 levels, the intratumor matured DCs and CD8+ T cells, the protein expresion of STING and IRF-3, and the secretion of IFN-β and IFN-γ. 

A STING pathway-activatable contrast agent for MRI-guided tumor immunoferroptosis synergistic therapy

Inflammatory bowel disease (IBD), including Crohn's disease (CD) and ulcerative colitis (UC), is a group of chronic inflammatory diseases of the gastrointestinal tract. Repeated inflammation can lead to complications, such as intestinal fistula, obstruction, perforation, and bleeding. Unfortunately, achieving durable remission and mucosal healing (MH) with current treatments is difficult. Stem cells (SCs) have the potential to modulate immunity, suppress inflammation, and have anti-apoptotic and pro-angiogenic effects, making them an ideal therapeutic strategy to target chronic inflammation and intestinal damage in IBD. In recent years, hematopoietic stem cells (HSCs) and adult mesenchymal stem cells (MSCs) have shown efficacy in treating IBD. In addition, numerous clinical trials have evaluated the efficiency of MSCs in treating the disease. This review summarizes the current research progress on the safety and efficacy of SC-based therapy for IBD in both preclinical models and clinical trials. We discuss potential mechanisms of SC therapy, including tissue repair, paracrine effects, and the promotion of angiogenesis, immune regulation, and anti-inflammatory effects. We also summarize current SC engineering strategies aimed at enhancing the immunosuppressive and regenerative capabilities of SCs for treating intestinal diseases. Additionally, we highlight current limitations and future perspectives of SC-related therapy for IBD. 

/pdf/stem-cell-therapy-in-inflammatory-bowel-disease-a-review-of-2a1ffhi2.pdf

Stem Cell Therapy in Inflammatory Bowel Disease: A Review of Achievements and Challenges

Activation of the cGAS-STING pathway combined with CRISPR-Cas9 gene editing triggering long-term immunotherapy.

Biomimetic dendritic polymeric microspheres induce enhanced T cell activation and expansion for adoptive tumor immunotherapy.

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Activation of the cGAS-STING pathway combined with CRISPR-Cas9 gene editing triggering long-term immunotherapy.

Biomimetic dendritic polymeric microspheres induce enhanced T cell activation and expansion for adoptive tumor immunotherapy.