Significance: Aberrant PD-1 expression is known to inhibit T cell effector activity and plays a pivotal role in tumor immune escape. Since maintaining an appropriate level of PD-1 expression is of great significance, it should be highly regulated at multiple levels. Despite extensive studies to date on this topic, it remains unclear how PD-1 expression is precisely regulated at the posttranslation level both during T cell activation and among the tumor microenvironment. Here, we show that KLHL22 maintains PD-1 protein homeostasis by degrading incompletely glycosylated PD-1, thereby preventing excessive T cell suppression. KLHL22-mediated degradation of PD-1 protein will be ineffective in response to either the tumor microenvironment or treatment with 5-FU, resulting in excessive PD-1 accumulation and reduced T cell activity.

Background: As the most widespread mRNAs modification, N6‐methyladenosine (m⁶A) is dynamically and reversibly modulated by methyltransferases and demethylases. ALKBH5 is a major demethylase, and plays vital roles in the progression of cancers. However, the role and mechanisms of ALKBH5 in colorectal cancer (CRC) is unclear.Results: Herein, we discovered that in CRC, downregulated ALKBH5 was closely related to poor prognosis of CRC patients. Functionally, our results demonstrated that knockdown of ALKBH5 enhanced the proliferation, migration and invasion of LOVO and RKO in vitro, while overexpression of ALKBH5 inhibited the functions of these cells. The results also demonstrated that knockdown of ALKBH5 promoted subcutaneous tumorigenesis of LOVO in vivo, while overexpression of ALKBH5 suppressed this ability. Mechanistically, results from joint analyses of MeRIP‐seq and RNA‐seq indicated that PHF20 mRNA was a key molecule that was regulated by ALKBH5‐mediated m⁶A modification. Further experiments indicated that ALKBH5 may inhibit stability of PHF20 mRNA by removing the m⁶A modification of PHF20 mRNA 3′UTR.Conclusions: ALKBH5 suppresses CRC progression by decreasing PHF20 mRNA methylation. ALKBH5‐mediated m⁶A modification of PHF20 mRNA can serve as a hopeful strategy for the intervention and treatment of CRC.

Emerging studies have focused on ways to treat cancers by modulating T cell activation. However, whether B cell receptor signaling in the tumor microenvironment (TME) can be harnessed for immunotherapy is unclear. Here, we report that an Asia-specific variant of human IgG1 containing a Gly396 to Arg396 substitution (hIgG1-G396R) conferred improved survival of patients with colorectal cancer (CRC). Mice with knockin of the murine functional homolog mIgG2c-G400R recapitulated the alleviated tumorigenesis and progression in murine colon carcinoma models. Immune profiling of the TME revealed broad mobilizations of IgG1⁺ plasma cells, CD8⁺ T cells, CD103⁺ DCs, and active tertiary lymphoid structure formation, suggesting an effective antitumor microenvironment in hIgG1-G396R CRC patients. Mechanistically, this variant potentiated tumor-associated antigen–specific (TAA-specific) plasma cell differentiation and thus antibody production. These elevated TAA-specific IgG2c antibodies in turn efficiently boosted the antibody-dependent tumor cell phagocytosis and TAA presentation to effector CD8⁺ T cells. Notably, adoptive transfer of TAA-specific class-switched memory B cells harboring this variant exhibited therapeutic efficacy in murine tumor models, indicating their clinical potential. All these results prompted a prospective investigation of hIgG1-G396R in patients with CRC as a biomarker for clinical prognosis and demonstrated that manipulating the functionality of IgG1⁺ memory B cells in tumors could improve immunotherapy outcomes.

False-positive findings of mediastinal lymph node often confound the image interpretation of the preoperative PET/CT in non–small cell lung cancer. In this case, we reported ¹⁸F-FDG and ⁶⁸Ga-FAPI PET/CT findings in a patient with squamous cell lung cancer. ¹⁸F-FDG–based TNM stage was stage IIIA (T1bN2M0) due to increased uptake in the enlarged right lower paratracheal lymph node. However, no abnormal ⁶⁸Ga-FAPI uptake was observed in this lymph node. Subsequent histopathological examination revealed no evidence of malignancy in the mediastinal lymph nodes. Therefore, the tumor stage was downstaged to stage IA (T1bN0M0), which was in accordance with ⁶⁸Ga-FAPI–based TNM stage.

Lactate, once dismissed as a mere by‐product of cancer metabolism, has emerged as a pivotal factor in tumor progression, exerting diverse effects on metabolic reprogramming and immune modulation. Lactate enhances tumor cell adaptability through sustained glycolysis and concurrently shapes the tumor microenvironment by modulating immune, stromal, and endothelial cell function. This review highlights the evolving understanding of lactate's role, extending beyond the Warburg effect to its regulatory capacity via lactylation, a recently identified post‐translational modification. The complex interaction between lactate and tumor biology is examined, emphasizing its influence on the tumor microenvironment and immune dynamics. Additionally, potential therapeutic strategies targeting lactate metabolism and transport are explored, along with lactylation regulation by histone‐modifying enzymes. Inhibitors targeting lactate production and transport, especially those against lactate dehydrogenase (LDH) and monocarboxylate transporters (MCTs), have shown considerable potential in preclinical and early clinical studies. Recent advancements are discussed, underscoring the potential of integrating metabolic regulation with immunotherapies, thereby offering a dual pathway in cancer treatment. These insights establish lactate and lactylation as pivotal modulators of tumor biology and highlight their potential as targets in precision oncology.