Polystyrene microplastics with absorbed nonylphenol induce intestinal dysfunction in human Caco-2 cells.

Due to the massive production and use of plastic, the chronic and evolving exposure to microplastics in our daily lives is omnipresent. Nonylphenol (NP), a persistent organic pollutant, may change toxicity when it co-exists with microplastics. In this study, polystyrene microplastics (PS-MPs), either alone or with pre-absorbed NP, generated oxidative stress and inflammatory lesions to Caco-2 cells, as well as affecting proliferation via the MAPK signaling pathway and causing apoptosis. Damage to cell membrane integrity and intestinal barrier (marked by lower transepithelial electric resistance, greater bypass transport, and tight junction structural changes) leads to enhanced internalization risk of PS-MPs. Some important intestinal functions including nutrient absorption and xenobiotic protection were also harmed. It is worth noting that the exposure of PS-MPs with a diameter of 0.1 µm improved intestinal functions quickly but acted as a chemosensitizer for a long time, inhibiting cell perception of other toxic substances and making the cells more vulnerable.

Targeting of focal adhesion kinase enhances the immunogenic cell death of PEGylated liposome doxorubicin to optimize therapeutic responses of immune checkpoint blockade.

BACKGROUNDS: Immune checkpoint blockade (ICB) is widely considered to exert long-term treatment benefits by activating antitumor immunity. However, many cancer patients show poor clinical responses to ICB due in part to the lack of an immunogenic niche. Focal adhesion kinase (FAK) is frequently amplified and acts as an immune modulator across cancer types. However, evidence illustrates that targeting FAK is most effective in combination therapy rather than in monotherapy. METHODS: Here, we used drug screening, in vitro and in vivo assays to filter out that doxorubicin and its liposomal form pegylated liposome doxorubicin (PLD) showed synergistic anti-tumor effects in combination with FAK inhibitor IN10018. We hypothesized that anti-tumor immunity and immunogenic cell death (ICD) may be involved in the treatment outcomes through the data analysis of our clinical trial testing the combination of IN10018 and PLD. We then performed cell-based assays and animal studies to detect whether FAK inhibition by IN10018 can boost the ICD of PLD/doxorubicin and further established syngeneic models to test the antitumor effect of triplet combination of PLD, IN10018, and ICB. RESULTS: We demonstrated that the combination of FAK inhibitor IN10018, and PLD/doxorubicin exerted effective antitumor activity. Notably, the doublet combination regimen exhibited response latency and long-lasting treatment effects clinically, outcomes frequently observed in immunotherapy. Our preclinical study confirmed that the 2-drug combination can maximize the ICD of cancer cells. This approach primed the tumor microenvironment, supplementing it with sufficient tumor-infiltrating lymphocytes (TILs) to activate antitumor immunity. Finally, different animal studies confirmed that the antitumor effects of ICB can be significantly enhanced by this doublet regimen. CONCLUSIONS: We confirmed that targeting FAK by IN10018 can enhance the ICD of PLD/doxorubicin, further benefiting the anti-tumor effect of ICB. The animal tests of the triplet regimen warrant further discovery in the real world.