In humans, Interleukin-8 (IL-8 or CXCL8) is a granulocytic chemokine with multiple roles within the tumor microenvironment (TME), such as recruiting immunosuppressive cells to the tumor, increasing tumor angiogenesis, and promoting epithelial-to-mesenchymal transition (EMT). All of these effects of CXCL8 on individual cell types can result in cascading alterations to the TME. The changes in the TME components such as the cancer-associated fibroblasts (CAFs), the immune cells, the extracellular matrix, the blood vessels, or the lymphatic vessels further influence tumor progression and therapeutic resistance. Emerging roles of the microbiome in tumorigenesis or tumor progression revealed the intricate interactions between inflammatory response, dysbiosis, metabolites, CXCL8, immune cells, and the TME. Studies have shown that CXCL8 directly contributes to TME remodeling, cancer plasticity, and the development of resistance to both chemotherapy and immunotherapy. Further, clinical data demonstrate that CXCL8 could be an easily measurable prognostic biomarker in patients receiving immune checkpoint inhibitors. The blockade of the CXCL8-CXCR1/2 axis alone or in combination with other immunotherapy will be a promising strategy to improve antitumor efficacy. Herein, we review recent advances focusing on identifying the mechanisms between TME components and the CXCL8-CXCR1/2 axis for novel immunotherapy strategies.

Harmine is a naturally occurring β-carboline alkaloid originally isolated from Peganum harmala. As a major active component, harmine exhibits a broad spectrum of pharmacological properties, particularly remarkable antitumor effects. Recent mechanistic studies have shown that harmine can inhibit cancer cell proliferation and metastasis through epithelial-to-mesenchymal transition, cell cycle regulation, angiogenesis, and the induction of tumor cell apoptosis. Furthermore, harmine reduces drug resistance when used in combination with chemotherapeutic drugs. Despite its remarkable antitumor activity, the application of harmine is limited by its poor solubility and toxic side effects, particularly neurotoxicity. Novel harmine derivatives have demonstrated strong clinical application prospects, but further validation based on drug activity, acute toxicity, and other aspects is necessary. Here, we present a review of recent research on the action mechanism of harmine in cancer treatment and the development of its derivatives, providing new insights into its potential clinical applications and strategies for mitigating its toxicity while enhancing its efficacy.

There is an urgent need for the development of safe and effective modalities for the treatment of diseases owing to drug resistance, undesired side effects, and poor clinical outcomes. Combining cell-targeting and efficient cell-killing properties, peptide-drug conjugates (PDCs) have demonstrated superior efficacy compared with peptides and payloads alone. However, innovative molecular designs of PDCs are essential for further improving targeting precision, protease resistance and stability, cell permeability, and overall treatment efficacy. Several strategies have been developed to address these challenges, such as multivalency approaches, bispecific targeting, and long-acting PDCs. Other novel strategies, including overcoming biological barriers, conjugating novel functional payloads, and targeting macropinocytosis, have also shown promise. This perspective compiles the most recent strategies for enhancing PDC treatment efficacy, highlights key advancements in PDC, and provides insights on future directions for the development of novel PDCs.

Cancer-associated fibroblasts (CAFs) are essential components of the tumor microenvironment. Fibroblast activation protein (FAP) is overexpressed in CAFs. FAP-targeted molecular imaging agents, including the FAP inhibitors (FAPIs), have shown promising results in tumor diagnosis. We aimed to design a Gd-labeled FAPI Dimer, Gd-DOTA-Suc-Lys-(FAPI04)₂, to optimize the pharmacokinetics and evaluate its potential capacity for targeting FAP-positive solid tumors in vivo. The Gd-labeled FAPI Dimer was successfully synthesized with exceeding 98% purity. Preclinical pharmacokinetics were determined in assessed FAP-positive U87 cell-derived xenografts and FAP-negative C6-derived xenografts using small-animal T1-weighted 7.0T MR imaging. The longitudinal correlation coefficient (r1) of the agent was 3.813 mM^-1·S^-1. The administration of the Gd-FAPI04 Dimer probe showed a notable enhancement of tumor contrast on T1-weighted whole-body MRI. At 10 and 30 minutes post-injection, the U87 subcutaneous tumor demonstrated significantly greater contrast enhancement than the C6 subcutaneous tumor (P <0.05). In vivo, the safety of the Gd-FAPI-04 Dimer probe was evaluated, which showed no tissue damage in vital organs like the heart, liver, spleen, lung, and kidneys, as indicated by unchanged morphology compared to a normal saline control group. The novel Gd-FAPI04 Dimer molecular probe, Gd-DOTA-Suc-Lys-(FAPI-04)₂ specifically targeting FAP may serve as a safe and promising tool for the diagnostic imaging of solid tumors.