Highlighted Research Articles

To identify immune determinants of clinical efficacy, Jiang and colleagues analyzed biopsies from patients with HPV-positive oropharyngeal carcinoma, treated with ipilimumab and nivolumab. Responders showed a marked post-therapy reduction in the frequency of highly immunosuppressive effector Tregs (eTreg), which reshaped the tumor microenvironment and promoted reinvigoration of exhausted tumor-reactive CD8+ T cells and antitumor immunity. Pretreatment frequency of Fc gamma receptor IIIa (FCGR3A)-positive NK cells, capable of ipilimumab-dependent eTreg depletion, was the strongest predictor of reduced tumor viability per multivariable regression modeling. These findings support a critical role for eTreg depletion in the response to ipilimumab and provide rationale for Treg-focused immunotherapies in HPV-positive cancers.See article, p. 1569.Brain cancer is among the most lethal and difficult to detect cancers using blood-based assays, limiting early diagnosis. Mathios, Niknafs, and colleagues developed a machine learning method that analyzes genome-wide cell-free DNA (cfDNA) fragmentation features for noninvasive detection. cfDNA fragmentome analyses accurately identified gliomas across all grades and revealed signatures derived from both tumor DNA and changes in immune cell populations linked to tumor-induced immunosuppression. These results highlight cfDNA fragmentomic analysis as a promising strategy for blood-based detection of brain cancer.See article, p. 1593.Circulating tumor DNA (ctDNA) analysis and radiomic image analysis are promising noninvasive cancer biomarkers, but the complementarity of these approaches and the clinical efficacy of integrating these data has not been demonstrated. Moding and colleagues showed that mid-treatment ctDNA levels predicted outcomes in patients undergoing chemoradiation therapy for non–small cell lung cancer. Combining analysis of mid-treatment ctDNA, radiomics, and tumor features in a dynamic risk model improved outcome prediction. These findings suggest that integrating noninvasive biomarkers could enable response-adapted cancer therapies.See article, p. 1609.The microbial signature of multifocal hepatocellular carcinoma (HCC) remains poorly understood. Lu, Xu, Chen, and colleagues applied multiomic sequencing in multifocal HCC tumor tissue, revealing heterogeneous microbial communities among HCC tumor nodules. The microbial characteristics differed distinctly between intrahepatic metastases (IM) and multicentric occurrence (MO) subtypes. A nine-bacterium biomarker panel distinguished IM and MO nodules with an AUROC of 0.795. The IM-enriched bacteria E. faecalis and S. anginosus promoted HCC cell migration, invasion, and tumor progression in mice by inducing immunosuppressive microenvironments and an epithelial–mesenchymal transition. These findings highlight the necessity of considering bacterial heterogeneity as biomarkers and targets for multifocal HCC therapeutic intervention.See article, p. 1630.Colorectal cancer is a genetically heterogeneous disease with stepwise progression. Chen, Cai, Hu, Tan, Lu, Zhu, and colleagues delineated the cellular and molecular alterations during colorectal cancer evolution and generated a high-resolution single-cell expression quantitative trait loci (sc-eQTL) map, uncovering regulatory variants missed in bulk analyses. A polygenic risk score analysis from sc-eQTLs markedly improved risk prediction. The sc-eQTL variant rs4794979 conferred increased colorectal cancer risk by specifically promoting LGALS9 expression in stem-like cells, driving cancer-associated fibroblast activation and CD8+ T cell exhaustion via cell–cell interactions. This study provides a valuable resource to understand genetic control at cell-subtype resolution and sheds light on the cellular crosstalk mechanisms during colorectal cancer development.See article, p. 1649.To cope with metabolic stress in the tumor, tumoral immune cells upregulate CD36 for lipid uptake, impairing antitumor immunity. This enhances the survival and suppressive activity of regulatory T cells, while increasing the susceptibility of CD8+ T cells to ferroptosis and exhaustion. Tzeng, Yu, and colleagues developed a humanized anti-CD36 IgG4 antibody targeting the CD36 lipid-binding domain. This antibody exhibited excellent safety and pharmacokinetics in mice and cynomolgus monkeys, inducing strong antitumor immunity alone or with PD-L1 blockade for HCC and liver metastases. It also reprogrammed the immune landscape of human HCC ex vivo, marking it as a first-in-class immunotherapy targeting CD36.See article, p. 1676.Mutations in the KRAS oncogene are present in most patients with pancreatic ductal adenocarcinoma (PDAC). Orlen and colleagues examined the antitumor activity of RAS(ON) multi-selective inhibitors that act by inhibiting all RAS family members, including wild-type RAS, in the GTP-bound (ON) state. In immunocompetent mouse models, RAS inhibition dramatically reshaped the tumor microenvironment, leading to tumor regressions whose depth and duration was T-cell–dependent. Immunotherapy further augmented these antitumor effects. The findings provide a rationale for combining RAS(ON) multi-selective inhibitors with immune modulation in PDAC.See article, p. 1697.Building on previous studies that have suggested the efficacy of combining MEK or ERK inhibitors with CDK4/6 inhibition in the treatment of PDAC, Broderick, Mezzadra, and colleagues explored the therapeutic potential of combining CDK4/6 inhibitors with a RAS(ON) multi-selective inhibitor, demonstrating that CDK4/6 inhibition with palbociclib elicited an antitumor effect by driving tumor cells that could otherwise survive RAS inhibition alone towards a senescent-like state. The combination rewired the tumor immune microenvironment, and the addition of CD40 agonism to combined RAS and CDK4/6 inhibition further promoted durable tumor regression and disease control in a CD4+ T-cell–dependent manner. This study highlights the importance of CD4+ T cells in this therapeutic effect and suggests a promising combinatorial regimen for PDAC.See article, p. 1717.PDAC features a stiff, fibrotic tumor microenvironment (TME) that promotes tumor progression. Xie, Yu, Yang, Ke, Wang, and colleagues identified PYK2 (PTK2B) as a key immunomechanical checkpoint regulating monocyte-to-macrophage differentiation in PDAC. Mechanical cues sensed via Piezo1 and integrins were shown to activate PYK2, triggering F-actin polymerization and nuclear translocation. PYK2 then regulated genes such as ACTR3 and RELA, driving mechanotransduction and differentiation. Targeted Ptk2b deletion disrupts this process, reduces TME fibrosis, and enhances the efficacy of anti–PD-1 immunotherapy. These findings highlight PYK2 as a promising therapeutic target to improve immunotherapy outcomes in patients with PDAC.See article, p. 1740.