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Abstract Objectives Emerging evidence has demonstrated that tumour budding (TB) is negatively associated with T‐lymphocyte infiltration in CRC. Despite extensive research, the molecular characteristics of immunologically ‘hot’ TB remain poorly understood. Methods We quantified the number of TB by haematoxylin–eosin (H&E) sections and the densities of CD3+ and CD8+ T‐lymphocytes by immunohistochemistry in a CRC cohort of 351 cases who underwent curative resection. We analysed the differential expression and T‐lymphocyte infiltration score of 37 human epithelial keratins in CRC using RNA sequencing from the TCGA dataset. In 278 TB‐positive cases, KRT17 expression was evaluated in tumour centre (TC) and TB with a staining score. Patient demographic, clinicopathological features and survival rates were analysed. Results In a CRC cohort of 351 cases, low‐grade TB was associated with high CD3+ and CD8+ T‐cell densities in the invasive margin (IM) but not in the TC. Of 37 human epithelial keratins, only KRT17 expression in TB had an apparent association with TB‐grade and T‐lymphocyte infiltration. In 278 TB‐positive cases, high KRT17 expression in TB (KRT17TB) was negatively associated with low‐grade TB and positively associated with high CD3+ and CD8+ T‐cell densities in IM. High KRT17TB predicted early tumour grade, absence of lymph node metastasis and absence of tumour deposits. Additionally, patients with high KRT17TB had good overall survival and disease‐free survival. Notably, low KRT17TB can specifically identify those patients with a poor prognosis among colorectal cancer patients with low TB and high T‐lymphocyte infiltration. Conclusions KRT17 can be employed as a new indicator for distinguishing different immunological TBs.

Abstract High lymphocyte infiltration and immunosuppression characterize the tumor microenvironment (TME) in renal cell carcinoma (RCC). There is an urgent need to elucidate how tumor cells escape the immune attack and to develop novel therapeutic targets to enhance the efficacy of immune checkpoint blockade (ICB) in RCC. Overactivated IFN‐γ‐induced JAK/STAT signaling involves in such TME, but the underlying mechanisms remain elusive. Here, EH domain‐binding protein 1‐like protein 1 (EHBP1L1) is identified as a crucial mediator of IFN‐γ/JAK1/STAT1/PD‐L1 signaling in RCC. EHBP1L1 is highly expressed in RCC, and high EHBP1L1 expression levels are correlated with poor prognosis and resistance to ICB. EHBP1L1 depletion significantly inhibits tumor growth, which is attributed to enhanced CD8+ T cell‐mediated antitumor immunity. Mechanistically, EHBP1L1 interacts with and stabilizes JAK1. By competing with SOCS1, EHBP1L1 protects JAK1 from proteasomal degradation, which leads to elevated JAK1 protein levels and JAK1/STAT1/PD‐L1 signaling activity, thereby forming an immunosuppressive TME. Furthermore, the combination of EHBP1L1 inhibition and ICB reprograms the immunosuppressive TME and prevents tumor immune evasion, thus significantly reinforcing the therapeutic efficacy of ICB in RCC patient‐derived xenograft (PDX) models. These findings reveal the vital role of EHBP1L1 in immune evasion in RCC, which may be a potential complement for ICB therapy.

Abstract The roles of oncogenic KRAS in tumor immune evasion remain poorly understood. Here, mutant KRAS is identified as a key driver of tumor immune evasion in colorectal cancer (CRC). In human CRC specimens, a significant reduction in cytotoxic CD8+ T‐cell tumor infiltration is found in patients with mutant versus wild type KRAS. This phenomenon is confirmed by preclinical models of CRC, and further study showed KRAS mutant tumors exhibited poor response to anti‐PD‐1 and adoptive T‐cell therapies. Mechanistic analysis revealed lactic acid derived from mutant KRAS‐expressing tumor cells sensitized tumor‐specific cytotoxic CD8+ T‐cells to activation‐induced cell death via NF‐κB inactivation; this may underlie the inverse association between intratumoral cytotoxic CD8+ T‐cells and KRAS mutation. Importantly, KRAS mutated tumor resistance to immunotherapies can be overcome by inhibiting KRAS or blocking lactic acid production. Together, this work suggests the KRAS‐mediated immune program is an exploitable therapeutic approach for the treatment of patients with KRAS mutant CRC.

Adipose‐derived stem cells (ADSCs) play a vital role in colorectal cancer (CRC) progression, but the mechanism remains largely unknown. Herein, we found that ADSCs isolated from CRC patients produced more cysteine‐rich 61 (Cyr61) than those from healthy donors, and the elevated serum Cyr61 levels were associated with advanced TNM stages. Moreover, serum Cyr61 displayed a better diagnostic value for CRC compared to carcinoembryonic antigen (CEA) and carbohydrate antigen (CA19‐9). Mechanistically, integrin αVβ5 was identified as the functional receptor by which Cyr61 promotes CRC cell metastasis in vitro and in vivo by activating the αVβ5/FAK/NF‐κB signaling pathway. In addition, Cyr61 promotes vasculogenic mimicry (VM) formation, thereby promoting tumor growth and metastasis through a αVβ5/FAK/HIF‐1α/STAT3/MMP2 signaling cascade. Histologically, xenografts and clinical samples of CRC both exhibited VM, which was correlated with HIF‐1α and MMP2 activation. Notably, we demonstrated the synergistic effect of combined anti‐VM therapy (integrin αVβ5 inhibitor) and anti‐VEGF therapy (bevacizumab) in patient‐derived xenograft models. Further investigation showed that CRC cell‐derived exosomal STAT3 promoted Cyr61 transcription in ADSCs. These findings indicate that Cyr61 derived from ADSCs plays a critical role in promoting CRC progression via integrin αVβ5 and provides a novel antitumor strategy by targeting Cyr61/αVβ5.