Triple-negative breast cancer (TNBC) poses as a daunting and intricate manifestation of breast cancer, highlighted by few treatment options and a poor outlook. The crucial element in fostering tumor growth and immune resistance is the polarization of tumor-associated macrophages (TAMs) into the M2 state within the tumor microenvironment (TME). To address this, we developed M2 targeting peptide-chitosan-curcumin nanoparticles (M2pep-Cs-Cur NPs), a targeted delivery system utilizing chitosan (Cs) as a carrier, curcumin (Cur) as a therapeutic agent, and targeting peptides for specificity. These NPs effectively inhibited TNBC cell proliferation (~ 70%) and invasion (~ 70%), while increasing the responsiveness of tumors to anti-PD-L1 treatment (~ 50% survival enhancement) in vitro and in vivo. Bioinformatics analysis suggested that Cur modulates TAM polarization by influencing key genes such as COX-2, offering insights into its underlying mechanisms. This study highlights the potential of M2pep-Cs-Cur NPs to reverse M2 polarization in TAMs, providing a promising targeted therapeutic strategy to overcome immunotherapy resistance and improve TNBC outcomes.
© 2025. The Author(s).

Limited immune infiltration within the tumor microenvironment (TME) hampers the efficacy of immune checkpoint blockade (ICB) therapy. To enhance immune infiltration, mild photothermal therapy (PTT) is often combined with immunotherapy. However, the impact of mild PTT on the TME remains unclear. The bioinformatics analyses reveal that mild PTT amplifies immune cell infiltration and stimulates T-cell activity. Notably, it accelerates the release of tumor cell-derived exosomes (TEX) and upregulates PD-L1 expression on both tumor cells and TEX. Consequently, it is proposed that locally inhibiting TEX release is crucial for overcoming the adverse effects of mild PTT, thereby enhancing ICB therapy. Thus, a multi-stage drug delivery system is designed that concurrently delivers photosensitizers (reduced graphene oxide nanosheets, NRGO), anti-PD-L1 antibodies, and exosome inhibitors (sulfisoxazole). The system employs a temperature-sensitive lipid gel as the primary carrier, with NRGO serving as a secondary carrier that supports photothermal conversion and incorporation of sulfisoxazole. Importantly, controlled drug release is achieved using near-infrared radiation. The findings indicate that this local combination therapy remodels the immunosuppressive TME through exosome inhibition and enhanced immune cell infiltration, while also boosting T-cell activity to trigger systemic antitumor immunity, showcasing the remarkable efficacy of this combination strategy in eradicating cold tumors.
© 2024 The Author(s). Advanced Science published by Wiley‐VCH GmbH.

Immune cells experience large cell shape changes during environmental patrolling because of the physical constraints that they encounter while migrating through tissues. These cells can adapt to such deformation events using dedicated shape-sensing pathways. However, how shape sensing affects immune cell function is mostly unknown. Here, we identify a shape-sensing mechanism that increases the expression of the chemokine receptor CCR7 and guides dendritic cell migration from peripheral tissues to lymph nodes at steady state. This mechanism relies on the lipid metabolism enzyme cPLA2, requires nuclear envelope tensioning and is finely tuned by the ARP2/3 actin nucleation complex. We also show that this shape-sensing axis reprograms dendritic cell transcription by activating an IKKβ-NF-κB-dependent pathway known to control their tolerogenic potential. These results indicate that cell shape changes experienced by immune cells can define their migratory behavior and immunoregulatory properties and reveal a contribution of the physical properties of tissues to adaptive immunity.
© 2024. The Author(s).

Immune cells experience large deformation events while patrolling their environment. These cell shape changes arise from the physical constraints encountered during migration within and between tissues. It has become increasingly clear that these cells can survive and adapt to these changes in cell shape using dedicated shape sensing pathways. However, how shape sensing impacts their behavior and function remains largely unknown. Here we identify a shape sensing mechanism that couples dendritic cell motility to expression of CCR7, the chemokine receptor guiding their migration from the periphery to lymph nodes. We found that this mechanism relies on the lipid metabolism enzyme cPLA 2 , requires nuclear envelop unfolding and tension and is finely tuned by the Arp2/3 actin nucleation complex. We further observed that shape sensing through the Arp2/3-cPLA 2 axis leads to Ikkb-NFkB-dependent transcriptional reprogramming of dendritic cells, which was shown to control their migration to lymph node and tolerogenic function at steady-state. Our results highlight that cell shape changes experienced by immune cells can define their migratory behavior and immunoregulatory properties, revealing the contribution of the physical properties of tissues to adaptive immunity.

Acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) is a common life-threatening syndrome with no effective pharmacotherapy. Sepsis-related ARDS is the main type of ARDS and is more fatal than other types. Extracellular vesicles (EVs) are considered novel mediators in the development of inflammatory diseases. Our previous research suggested that endothelial cell-derived EVs (EC-EVs) play a crucial role in ALI/ARDS development, but the mechanism remains largely unknown. Here, we demonstrated that the number of circulating EC-EVs was increased in sepsis, exacerbating lung injury by targeting monocytes and reprogramming them towards proinflammatory macrophages. Bioinformatics analysis and further mechanistic studies revealed that vascular cell adhesion molecule 1 (VCAM1), overexpressed on EC-EVs during sepsis, activated the NF-κB pathway by interacting with integrin subunit alpha 4 (ITGA4) on the monocyte surface, rather than the tissue resident macrophage surface, thereby regulating monocyte differentiation. This effect could be attenuated by decreasing VCAM1 levels in EC-EVs or blocking ITGA4 on monocytes. Furthermore, the number of VCAM1+ EC-EVs was significantly increased in patients with sepsis-related ARDS. These findings not only shed light on a previously unidentified mechanism underling sepsis-related ALI/ARDS, but also provide potential novel targets and strategies for its precise treatment.
© 2024 The Authors. Journal of Extracellular Vesicles published by Wiley Periodicals LLC on behalf of International Society for Extracellular Vesicles.