As a key glycolysis enzyme, the significance of pyruvate dehydrogenase kinase 1 (PDK1) in the development of colorectal cancer (CRC) remains unknown. This study revealed that the prognosis of CRC patients with high levels of PDK1 was poor, and PDK1 knockdown significantly reduced liver metastasis of CRC in both nude mice and immune competent BALB/C mice. When combined with cryptotanshinone (CPT), an inhibitor of STAT3-p-Y705, the liver metastasis was further inhibited. PDK1 knockdown obviously increased reactive oxygen species level in anoikis conditions and subsequently resulted in an elevated anoikis, but the combination of PDK1 knockdown and CPT showed a reduced effect on anoikis. Based on this discrepancy, the adherence ability of CRC cells to matrix protein fibronectin was further detected. It showed that PDK1 knockdown significantly decreased the adherence of CRC cells to fibronectin when combined with CPT. These results suggest that inhibition of PDK1 can decrease the surviving CRC cells in blood circulation via up-regulation of anoikis, and inhibition of STAT3-p-Y705 can prevent it to settle down on the liver premetastatic niche, which ultimately reduces liver metastasis.

Adaptive resistance to immunotherapy remains a significant challenge in cancer treatment. The reshaping of the tumor immune microenvironment in response to therapeutic pressures is a crucial factor contributing to this resistance. In this study, by comprehensive metabolic profiling of tumor tissues, we identified elevated itaconate in response to anti–PD-1 therapy as an adaptive resistance mechanism that promoted immune escape and tumor progression. CD8+ T-cell–derived IFNγ induced a significant upregulation of cis-aconitate decarboxylase 1 (ACOD1) in macrophages via the JAK–STAT1 pathway, thereby rewiring the Krebs cycle toward itaconate production. In murine models, macrophage-specific deletion of Acod1 increased the antitumor efficacy of anti–PD-1 therapy and improved survival. Additionally, itaconate and its derivative, 4-octyl itaconate, suppressed the tumor antigen presentation and cross-priming ability of dendritic cells, resulting in the impairment of antigen-specific T-cell antitumor responses. In summary, these findings identify an IFNγ-dependent immunometabolic mechanism of anti–PD-1 resistance, providing a promising strategy for combination therapy. Significance: Elevated itaconate production by macrophages induced by IFNγ is a critical negative feedback immunoregulatory metabolic response to anti-PD-1 immunotherapy that inhibits the cross-priming function of dendritic cells and confers immunotherapy resistance.

Radioresistance is one of the important reasons for local recurrence and distant metastasis in non-small cell lung cancer (NSCLC). Itaconate primarily functions as an anti-inflammatory metabolite in macrophages, however, its role in radiotherapy remains to be explored. In this study, we demonstrated that radiation significantly increases itaconate in the tumor microenvironment (TME), which is produced by macrophages. Mechanistically, the NF-κB signaling pathway is rapidly activated in macrophages, which enhances the binding of P65 to the Acod1 promoter region, leading to significantly increased secretion of itaconate. Excessive itaconate alleviates oxidative stress of NSCLC cell lines by stabilizing NRF2 protein. Notably, specifically knocking out Acod1 on myeloid cells enhances the activation of the tumor immune microenvironment in response to radiotherapy, particularly increasing the infiltration and activation of CD8⁺ T cells. Therefore, we propose that targeting Acod1 could be an effective strategy to improve radiosensitivity in NSCLC.

The immunosuppressive tumor microenvironment (TME) drives radioresistance, but the role of γδ T cells in regulating radiosensitivity remains incompletely understood. In this study, we found that γδ T cell infiltration in the TME substantially increased after radiotherapy and contributed to radioresistance. Depletion of γδ T cells enhanced radiosensitivity. Single-cell RNA-seq revealed that γδ T cells in the postradiotherapy TME were characterized by the expression of Zbtb16 , Il23r , and Il17a , and served as the primary source of IL-17A. These γδ T cells promoted radioresistance by recruiting myeloid-derived suppressor cells and suppressing T cell activation. Mechanistically, radiotherapy-induced tumor cell–derived microparticles containing dsDNA activated the cGAS-STING/NF-κB signaling pathway in macrophages, upregulating the expression of the chemokine CCL20, which was critical for γδ T cell recruitment. Targeting γδ T cells and IL-17A enhanced radiosensitivity and improved the efficacy of radiotherapy combined with anti-PD-1 immunotherapy, providing potential therapeutic strategies to overcome radioresistance.

Despite advances in multimodal cancer therapy, such as combining radical surgery with high-intensity chemoradiotherapy, for SMARCB1/INI-1-deficient sinonasal carcinoma (SDSC), the prognosis of patients remains poor. Immunotherapy is gaining increasing popularity as a novel treatment strategy for patients with SMARCB1/INI-1-deficient tumors. Herein, we report on the management of three patients with SDSC who received PD-1/PD-L1 inhibitor therapy as a part of multimodal therapy based on surgery and chemoradiotherapy. All three patients survived and demonstrated good clinical remission and disease control. To our knowledge, this is the first case series reporting the use of immunotherapy to improve clinical outcomes in neoadjuvant, adjuvant, and late first-line stages of treatment in patients with SDSC. Furthermore, we reviewed the relevant literature and further explored the correlation between SMARCB1/INI-1 deletion and immunotherapy.