Background: Anti-angiogenic therapy has been widely applied to the clinical treatment of malignant tumors. However, the efficacy of such treatments has been called into question, especially in triple-negative breast cancer (TNBC). Bevacizumab, the first anti-angiogenic agent approved by FDA, actually increases invasive and metastatic properties of TNBC cells, resulting from the activation of Wnt/β-catenin signaling in response to hypoxia. As a critical receptor of Wnt/β-catenin signaling, Frizzled-7 (Fzd7) is aberrantly expressed in TNBC, indicating Fzd7 a potential target for developing drugs to be combined with anti-angiogenic agents. Methods: Hybridoma technique and antibody humanization technique were utilized to generate a Fzd7-targeting antibody (SHH002-hu1). Biolayer interferometry (BLI) assay and near infrared (NIR) imaging were conducted to detect the affinity and targeting ability of SHH002-hu1. Next, whether SHH002-hu1 could suppress the invasion and migration of TNBC cells induced by Bevacizumab were validated, and the underlying molecular mechanisms were elucidated by luciferase reporter and western blot assays. The nude-mice transplanted TNBC models were established to assess the anti-TNBC activities of SHH002-hu1 when combined with Bevacizumab. Then, the effects on putative TNBC stem-like cells and Wnt/β-catenin signaling were evaluated by immunofluorescence (IF). Further, the tumor-initiating and self-renew capacity of TNBC cells were studied by secondary nude mouse xenograft model and sphere formation assay. In addition, the effects of SHH002-hu1 on the adaptation of TNBC cells to hypoxia were evaluated by the detection of vasculogenic mimicry (VM) and hypoxia-inducible factor-1α (HIF-1α) transcriptional activity. Results: The novel humanized antibody targeting Fzd7 (SHH002-hu1) exhibited extremely high affinity with Fzd7, and specifically targeted to Fzd7⁺ cells and tumor tissues. SHH002-hu1 repressed invasion, migration and epithelial-mesenchymal cell transformation (EMT) of TNBC cells induced by Bevacizumab through abating Wnt/β-catenin signaling. SHH002-hu1 significantly enhanced the capacity of Bevacizumab to inhibit the growth of TNBC via reducing the subpopulation of putative TNBC stem-like cells, further attenuating Bevacizumab-enhanced tumor-initiating and self-renew capacity of TNBC cells. Moreover, SHH002-hu1 effectively restrained the adaptation of TNBC cells to hypoxia via disrupting Wnt/β-catenin signaling. Conclusion: SHH002-hu1 significantly enhances the anti-TNBC capacity of Bevacizumab, and shows the potential of preventing TNBC recurrence, suggesting SHH002-hu1 a good candidate for the synergistic therapy together with Bevacizumab.

Non–small‐cell lung cancer (NSCLC) is one of the deadliest cancers worldwide, and metastasis is considered one of the leading causes of treatment failure in NSCLC. Wnt/β‐catenin signaling is crucially involved in epithelial–mesenchymal transition (EMT), a crucial factor in promoting metastasis, and also contributes to resistance developed by NSCLC to targeted agents. Frizzled‐7 (Fzd7), a critical receptor of Wnt/β‐catenin signaling, is aberrantly expressed in NSCLC and has been confirmed to be positively correlated with poor clinical outcomes. SHH002‐hu1, a humanized antibody targeting Fzd7, was previously successfully generated by our group. Here, we studied the anti‐tumor effects of SHH002‐hu1 against NSCLC and revealed the underlying mechanism. First, immunofluorescence (IF) and near‐infrared (NIR) imaging assays showed that SHH002‐hu1 specifically binds Fzd7⁺ NSCLC cells and targets NSCLC tissues. Wound healing and transwell invasion assays indicated that SHH002‐hu1 significantly inhibits the migration and invasion of NSCLC cells. Subsequently, TOP‐FLASH/FOP‐FLASH luciferase reporter, IF, and western blot assays validated that SHH002‐hu1 effectively suppresses the activation of Wnt/β‐catenin signaling, and further attenuates the EMT of NSCLC cells. Finally, the subcutaneous xenotransplanted tumor model of A549/H1975, as well as the popliteal lymph node (LN) metastasis model, was established, and SHH002‐hu1 was demonstrated to inhibit the growth of NSCLC xenografts and suppress LN metastasis of NSCLC. Above all, SHH002‐hu1 with selectivity toward Fzd7⁺ NSCLC and the potential of inhibiting invasion and metastasis of NSCLC via disrupting Wnt/β‐catenin signaling, is indicated as a good candidate for the targeted therapy of NSCLC.

Alzheimer’s disease (AD) is characterized by β-amyloid plaques, neurofibrillary tangles, neuroinflammation, and oxidative stress—pathological features that pose significant challenges for the development of therapeutic interventions. Given these challenges, this review comprehensively evaluates the neuroprotective mechanisms of bioactive compounds derived from red algae, including polysaccharides and phycobiliproteins, which are considered a promising source of natural therapeutics for AD. Red algal constituents exhibit neuroprotective activities through multiple mechanisms. Sulfated polysaccharides (e.g., carrageenan, porphyran) suppress NF-κB-mediated neuroinflammation, modulate mitochondrial function, and enhance brain-derived neurotrophic factor (BDNF) expression. Phycobiliproteins (phycoerythrin, phycocyanin) and peptides derived from their degradation scavenge reactive oxygen species (ROS) and activate antioxidant pathways (e.g., Nrf2/HO-1), thus mitigating oxidative damage. Carotenoids (lutein, zeaxanthin) improve cognitive function through the inhibition of acetylcholinesterase and pro-inflammatory cytokines (TNF-α, IL-1β), while phenolic compounds (bromophenols, diphlorethol) provide protection by targeting multiple pathways involved in dopaminergic system modulation and Nrf2 pathway activation. Emerging extraction technologies—including microwave- and enzyme-assisted methods—have been shown to optimize the yield and maintain the bioactivity of these compounds. However, the precise identification of molecular targets and the standardization of extraction techniques remain critical research priorities. Overall, red algae-derived compounds hold significant potential for multi-mechanism AD interventions, providing novel insights for the development of therapeutic strategies with low toxicity.

Background: Hypoxia is associated with the evasion of triple-negative breast cancer (TNBC) from immune surveillance. Hypoxia increases the subpopulation of putative TNBC stem-like cells (TNBCSCs) through activating Wnt/β-Catenin signaling. The shedding of MHC class I-related chain A (MICA) is particularly noteworthy in cancer stem cells (CSCs), promoting the resistance of CSCs to natural killer (NK) cell cytotoxicity. To reestablish MICA/NKG2D-mediated immunosurveillance, we proposed the design of a fusion protein (SHH002-hu1-MICA) which consists of Frizzled-7 (Fzd7)-targeting antibody and MICA, serving as an engager retargeting NK cells against TNBCs, especially TNBCSCs. Methods: Opal multicolor immunohistochemistry staining was used to validate the expression of membrane MICA (mMICA) and existence of NK cells in TNBC tumors; flow cytometry (FCM) assay was used to detect the expression of Fzd7/mMICA on TNBCs. Biolayer interferometry (BLI) and surface plasmon resonance (SPR) assays were executed to assess the affinity of SHH002-hu1-MICA towards rhFzd7/rhNKG2D; near-infrared imaging assay was used to evaluate the targeting capability. A cytotoxicity assay was conducted to assess the effects of SHH002-hu1-MICA on NK cell-mediated killing of TNBCs, and FCM assay to analyze the effects of SHH002-hu1-MICA on the degranulation of NK cells. Finally, TNBC cell-line-derived xenografts were established to evaluate the anti-tumor activities of SHH002-hu1-MICA in vivo. Results: The expression of mMICA is significantly downregulated in hypoxic TNBCs and TNBCSCs, leading to the evasion of immune surveillance exerted by NK cells. The expression of Fzd7 is significantly upregulated in TNBCSCs and exhibits a negative correlation with the expression of mMICA and infiltration level of NK cells. On accurate assembly, SHH002-hu1-MICA shows a strong affinity for rhFzd7/rhNKG2D, specifically targets TNBC tumor tissues, and disrupts Wnt/β-Catenin signaling. SHH002-hu1-MICA significantly enhances the cytotoxicity of NK cells against hypoxic TNBCs and TNBCSCs by inducing the degranulation of NK cells and promotes the infiltration of NK cells in CD44^high regions within TNBC xenograft tumors, exhibiting superior anti-tumor activities than SHH002-hu1. Conclusions: SHH002-hu1-MICA maintains the targeting property of SHH002-hu1, successfully activates and retargets NK cells against TNBCs, especially TNBCSCs, exhibiting superior antitumor activities than SHH002-hu1. SHH002-hu1-MICA represents a promising new engager for NK cell-based immunotherapy for TNBC.

The Wnt/β-Catenin signaling pathway is highly conserved and initiated by a multiprotein signalosome complex. It is essential for embryonic development, organ formation, and tissue homeostasis. Abnormal Wnt signaling is found in many malignant tumors, and Wnt mutations are widely known to drive tumor initiation. Since the discovery of its oncogenic roles, numerous therapeutic agents have been developed, but none have been approved. This is attributed to the inherent structural characteristics of its core components and their role in normal tissue homeostasis. The majority of clinical drugs are occupancy-driven small molecule inhibitors, and most encounter challenges such as off-target effects and adverse toxicities. In recent years, targeted protein degradation (TPD) technology has emerged as a promising approach, offering a novel strategy for drug development targeting the Wnt/β-Catenin pathway. Utilizing this technology to degrade key proteins in the Wnt/β-Catenin pathway holds significant potential for inhibiting its oncogenic effects and restoring the cancer-immunity cycle (CI cycle). This review presents a systematic analysis of the “undruggability” of the Wnt/β-Catenin pathway and proposes potential strategies ranging from target selection to TPD application, with the aim of offering novel insights into overcoming this challenge.