Yuan Yin

Dysregulated metabolism and functions of immune cells in the tumor microenvironment (TME) are key factors contributing to cancer progression. As the core immune cells in TME, tumor-associated macrophages (TAMs) have become a central focus in metabolic research of TME, though underlying mechanisms are not fully elucidated. Here, we found that long-chain acyl-coenzyme A synthetase-3 (ACSL3) is highly expressed in TAMs and correlates with poor prognosis in colorectal cancer (CRC). ACSL3 depletion induces TAM ferroptosis and reprograms them toward an M1-like phenotype. We further revealed that ACSL3 undergoes lactylation in TAMs, and identified Sirtuin 7 (SIRT7) as its delactylase. Mechanistically, SIRT7 delactylates ACSL3 at lysine 679, restores its enzymatic function and reprograms lipid metabolism in TAMs. Importantly, lactylated and activated ACSL3 significantly protects TAMs from ferroptotic stress and sustains their immunosuppressive phenotype. On the contrary, inhibiting ACSL3 lactylation reprograms TAMs toward an M1-like phenotype, further restores T cell cytotoxicity and suppresses CRC progression. Collectively, these findings establish ACSL3 lactylation in TAMs as a crucial signaling event that enables ferroptosis resistance and maintains M2 polarization, thereby promoting CRC progression. This study provides the therapeutic potential of targeting SIRT7-mediated delactylation of ACSL3 in TAMs, offering a promising strategy for CRC therapy.

Tumour development and progression are driven by intricate interactions among various cell types within the tumour microenvironment (TME). Targeting a single cell type often fails to eradicate cancer, highlighting the need for strategies to co‐target multiple cell types. MicroRNA‐21‐5p, highly abundant in tumour cells and tumour‐associated macrophages (TAMs), exerts strong cancer‐promoting effects. Epidermal growth factor receptor (EGFR) is overexpressed in various cancer types, and programmed death‐ligand 1 (PD‐L1) is expressed predominantly by TAMs in multiple cancers. In this study, we developed a dual‐targeted engineered milk‐derived extracellular vesicles system (7D12/KN035‐iEVs), decorated with 7D12 (an EGFR nanobody) and KN035 (a PD‐L1 nanobody), to specifically deliver miR‐21‐5p inhibitors into EGFR ⁺ and/or PD‐L1 ⁺ tumour cells and TAMs, thereby inhibiting tumour progression while reprogramming immunosuppressive TME. Notably, this dual‐targeting nanomedicine synergistically inhibits tumour growth when combined with immunotherapy and radiotherapy. In summary, this mEV‐based nanomedicine represents a promising universal strategy for cancer treatment, offering a versatile platform for targeting multiple components of the TME.

Chemoresistance is not only related to tumor cells themselves, but also regulated by the interaction between cells in the tumor microenvironment (TME). However, the underlying mechanisms are not well understood. RAB22A, a member of the RAB family of small GTPases that was identified by our group previously as an oncogene in colorectal cancer (CRC). In this study, we demonstrated that elevated expression of RAB22A in CRC cells, particularly in chemoresistant CRC cells, is associated with increased exosome secretion and enhanced chemoresistance. Mechanistically, RAB22A augments exosome secretion by inhibiting the ubiquitination and degradation of pyruvate kinase type M2 (PKM2), then promoting the phosphorylation of synaptosome-associated protein 23 (SNAP-23). Furthermore, RAB22A not only directly promotes chemoresistance in CRC cells but also indirectly induces acquired drug resistance of other CRC cells in the TME by promoting the secretion of RAB22A-PKM2-rich exosomes, thereby triggering intercellular chemoresistance transmission. Together, we reveal an essential role of RAB22A-PKM2-SNAP-23 signaling cascade in exosome induction in chemoresistant CRC cells and intercellular chemoresistance transmission, highlighting that targeting the RAB22A/PKM2/pSNAP axis is a potential novel strategy to reverse chemoresistance, and suggest circulating exosomal RAB22A and PKM2 as markers to predict the efficacy of chemotherapy in CRC.

Radioresistance is a major challenge in tumor radiotherapy and involves in a mixture of cellular events, including ferroptosis, a new type of programmed cell death characterized by the excess accumulation of iron-dependent lipid peroxides. In the present study, we observed that surviving cancer tissues and cells after radiotherapy had significantly greater glutathione to oxidized glutathione (GSH/GSSG) ratios and lower lipid reactive oxygen species (ROS) and malondialdehyde (MDA) levels than nonirradiated tumors and cells. Untargeted lipidomic analyses revealed that oleic acid (OA) and palmitoleic acid (POA) were the most significantly upregulated unsaturated fatty acids in irradiated surviving cancer cells compared with those in control cancer cells irradiated with IR. Both OA and POA could protect cancer cells from the killing effects of the ferroptosis inducer erastin and RSL3, and OA had a stronger protective effect than POA, resulting in lower lipid ROS production than POA. Mechanistically, OA protected cells from ferroptosis caused by the accumulation of polyunsaturated fatty acid-containing phospholipids in an ACSL3-dependent manner. A mouse model demonstrated that ACSL3 knockdown combined with imidazole ketone erastin synergistically enhanced antitumor effects in radiation-resistant tumors in vivo. Our study reveals previously undiscovered associations between radiation and fatty acid metabolism and ferroptosis, providing a novel treatment strategy for overcoming cancer radioresistance.

Background: Different doses of radiotherapy (RT) exert diverse effects on tumor immunity, although the precise irradiation method remains unknown. This study sought to elucidate the influence of combining different doses of RT with immune checkpoint inhibitors (ICIs) on the infiltration of CD8⁺T cells within tumors, thereby augmenting the anti-tumor response.Methods: Constructing a mouse model featuring bilateral lung cancer tumors subjected to high and low dose irradiation, the analysis of RNA transcriptome sequencing data and immunohistochemical validation for tumors exposed to various dosages guided the selection of the optimal low-dose irradiation scheme. Subsequently, upon the integration of immune checkpoint inhibitors (ICIs) therapy, the infiltration of immune cells within the tumor was ascertained via immunohistochemistry (IHC) and flow cytometry (FCM). Finally, through bioinformatics analysis and experimental verification, potential strategies to bolster the anti-tumor immune response were investigated.Results: In comparison to the administration of 20Gy alone to the primary tumor, supplementing with 6Gy directed at the abscopal tumor produces a more pronounced abscopal response. The synergy of 20Gy, 6Gy, and ICIs markedly boosts the efficiency of ICIs. According to the findings from IHC and FCM studies, the triple therapy group exhibits a heightened infiltration of immune cells into the tumor, largely attributable to the augmented expression of CCL17 within the tumor under these irradiation regimens, which subsequently draws CD8+ T cells to infiltrate the tumor site, exerting cytotoxic effects.Conclusion: Our study shows that the combined application of 20Gy and 6Gy can enhance the infiltration of tumor CD8⁺T cells in mice and improve the effectiveness of immunotherapy.

Many studies have shown that tumor cells that survive radiotherapy are more likely to metastasize, but the underlying mechanism remains unclear. Here we aimed to identify epithelial–mesenchymal transition (EMT)‐related key genes, which associated with prognosis and radiosensitivity in rectal cancer. First, we obtained differentially expressed genes by analyzing the RNA expression profiles of rectal cancer retrieved from The Cancer Genome Atlas database, EMT‐related genes, and radiotherapy‐related databases, respectively. Then, Lasso and Cox regression analyses were used to establish an EMT‐related prognosis model (EMTPM) based on the identified independent protective factor Fibulin5 (FBLN5) and independent risk gene EHMT2. The high‐EMTPM group exhibited significantly poorer prognosis. Then, we evaluated the signature in an external clinical validation cohort. Through in vivo experiments, we further demonstrated that EMTPM effectively distinguishes radioresistant from radiosensitive patients with rectal cancer. Moreover, individuals in the high‐EMTPM group showed increased expression of immune checkpoints compared to their counterparts. Finally, pan‐cancer analysis of the EMTPM model also indicated its potential for predicting the prognosis of lung squamous cell carcinoma and breast cancer patients undergoing radiotherapy. In summary, we established a novel predictive model for rectal cancer prognosis and radioresistance based on FBLN5 and EHMT2 expressions, and suggested that immune microenvironment may be involved in the process of radioresistance. This predictive model could be used to select management strategies for rectal cancer.