A critical determinant of T cell anti-tumor function lies in their spatial interactions with adjacent cells, a dimension that remains largely elusive to conventional analytical approaches. Spatial multi-omics technologies are advancing our understanding of cancer immunity by resolving cellular interactions within intact tumor tissue contexts. Integrative profiling of spatial genomics, transcriptomics, proteomics and metabolomics enables multidimensional characterization of these biological processes, which respectively links clonal architecture to immune selection, delineates functional state transitions, quantifies cellular crosstalk and effector function, and identifies biochemical barriers. We propose an organizational framework where intratumoral immunity is governed by regions, which control immune cell access and retention under microenvironmental constraints, and functional niches, where proximity-dependent multicellular interactions drive immune activation, help, killing, or suppression. Translationally, we outline a paradigm in which discovery-grade spatial multi-omics define minimal architectural metrics measurable in clinical formalin-fixed, paraffin-embedded samples under robust quality control, with large-scale validation establishing reproducible biomarkers for patient stratification and companion diagnostics, potentially supporting mechanism-anchored intervention design and microstructural-guided immunotherapy.

Background Immune checkpoint blockade provides durable benefit in a subset of patients with advanced non-small cell lung cancer (NSCLC), but response rates remain limited after progression on standard systemic therapy. Stereotactic body radiotherapy (SBRT) may enhance tumor-antigen release and systemic immune activation, thereby improving the efficacy of PD-1 blockade. This multicenter, single-arm, phase II study evaluated the efficacy and safety of SBRT plus nivolumab in previously treated advanced NSCLC. Methods Eighty-three patients who had experienced disease progression after at least one line of standard systemic therapy were enrolled across nine centers. Patients received SBRT to the primary lung lesion or, in selected cases without a visible primary tumor, to an involved nodal lesion, followed by nivolumab. Patients with symptomatic bone metastases could receive prior bone radiotherapy. The primary endpoint was objective response rate (ORR) according to RECIST version 1.1. Secondary endpoints included duration of response, progression-free survival (PFS), overall survival (OS), and safety. Bone radiotherapy and biomarker analyses were exploratory. Results The ORR was 39.7% (95% confidence interval [CI], 29.4-51.1%), including complete responses in 10.8%, and the disease control rate was 61.4%. The median duration of response was 27.0 months. Median PFS and OS were 11.1 months and 25.9 months, respectively. Among the 36 patients with bone metastases, the exploratory ORR was 57.2% in those who received bone radiotherapy and 13.6% in those who did not. Elevated baseline alkaline phosphatase and urea levels were associated with poorer survival in exploratory analyses. Treatment-related adverse events occurred in 63.9% of patients, with grade 3-4 events in 4.8% and no treatment-related deaths. Conclusions SBRT plus nivolumab demonstrated encouraging and durable antitumor activity with manageable toxicity in previously treated advanced NSCLC. The findings concerning bone radiotherapy and serum biomarkers are exploratory and hypothesis-generating and require validation in prospective randomized studies.

Antitumor immunity depends on a self-reinforcing cancer-immunity cycle, yet many tumors evade critical steps and respond poorly to checkpoint blockade. Emerging evidence indicates that gut microbiota-derived systemic cues could influence these therapeutic outcomes, highlighting the gut-brain axis (GBA) as a potentially important regulatory framework in cancer immunity. In this review, we summarize how GBA-related signals may influence multiple stages of the cycle through interconnected neural, endocrine, microbial, and immune pathways. Current findings suggest that these impacts are highly context-dependent, and some microbiota-associated findings may reflect direct microbiota-immune crosstalk rather than strictly defined GBA-mediated regulation. Since most mechanistic evidence remains preclinical and superficial, cautious interpretation is required. Integrated multiomics approaches may help to clarify regulatory networks, support biomarker discovery, and inform patient stratification for future precision cancer immunotherapy.

In this issue of Cancer Cell, Bolli et al. leverage a newly developed neutrophil analysis framework to identify CCL3 as a conserved marker for tumor-associated neutrophils (TANs) across human and murine cancers. Using complementary genetic manipulation strategies, they demonstrate that neutrophil-derived CCL3 supports pro-tumor TAN survival within hypoxic tumor niches.

8006 Background: Brain metastases (BM) are common in patients (pts) with SCLC and are associated with poor outcomes. Tarlatamab, a bispecific T-cell engager (BiTE) immunotherapy, demonstrated superior overall survival versus CTx in pts with SCLC following progression on or after platinum-based CTx in the DeLLphi-304 study, including pts with history of BM (prior or current) at baseline (OS HR 0.45 [95% CI: 0.31–0.65]). Here we compare the intracranial efficacy of tarlatamab vs CTx. Methods: Pts were randomized 1:1 to receive tarlatamab or CTx (topotecan, lurbinectedin or amrubicin) as 2L treatment for SCLC. Pts with stable asymptomatic brain metastases were eligible; prior CNS treatment was required until protocol amendment 3. Baseline brain imaging by contrast enhanced MRI was mandatory for all pts at screening and repeated at all subsequent imaging assessments for pts with a history of BM at baseline. A post hoc analysis on intracranial efficacy was performed by BICR per mRANO-BM. Given that most pts had prior CNS treatment, specified outcomes were CR, non-CR/non-PD, and PD. Results: BM at baseline were present in 98/254 pts (39%) in the tarlatamab arm and 99/255 (39%) in the CTx arm, of whom 75/98 (77%) and 69/99 (70%) had prior CNS treatment, respectively. A CNS full analysis set (FAS) was specified to include pts who had both a baseline scan and ≥ 1 postbaseline scan (tarlatamab-67; CTx-56 pts). In pts in FAS, treatment with tarlatamab resulted in longer CNS PFS than CTx (median: 6.5 mos vs 4.2 mos; HR, 0.40 [95% CI: 0.24–0.66]; Table). CNS tumor shrinkage of ≥30% was observed in 56% of pts with tarlatamab vs 38% with CTx. CNS complete response was observed in 15% of pts with tarlatamab vs 5% with CTx, with longer CNS duration of complete response (DOCR) (not estimable [NE] vs 3.6 mo) and longer CNS duration of disease control (DODC) (8.2 vs 5.2 mo) for pts in the tarlatamab arm. Pts with BM at baseline had longer OS with tarlatamab vs CTx (median OS: 13.9 vs 6.8 mos; HR, 0.51 [95% CI: 0.34–0.74]). In pts with BM at baseline, treatment-emergent adverse events (TEAEs) of any grade (gr)/gr 3/gr 4/gr 5 occurred in 99%/38%/9%/7% for tarlatamab vs 100%/38%/40%/10% for CTx. In pts treated with tarlatamab, the incidence of CRS and ICANS was 54% and 9% in pts with BM at baseline vs 58% and 4% in pts without BM at baseline, respectively. Conclusions: Tarlatamab demonstrated increased intracranial efficacy with longer CNS PFS and OS vs CTx in pts with stable, treated and untreated asymptomatic BM. These results affirm tarlatamab as the 2L standard of care for SCLC, even in pts with BM. Clinical trial information: NCT05740566 . Tarlatamabn = 67 CTxn = 56 CNS PFS, mos (95% CI) 6.5 (4.3, 13.7) 4.2 (2.9, 5.5) CNS Complete Response, n (%) 10 (15%) 3 (5%) CNS DOCR, mos (95% CI) NE (2.9, NE) 3.6 (3.1, NE) CNS DODC, mos (95% CI) 8.2 (6.3, NE) 5.2 (4.2, 6.2) CNS tumor shrinkage of ≥30%, % (n/N) a 56% (9/16) 38% (5/13) a Assessed in pts with ≥1 lesion that was ≥ 10 mm.

BACKGROUND:Various methods have been widely utilized to estimate the genomic breeding values (GEBVs) for genomic prediction. Traditional approaches often relied on the assumption of linear regression models, which struggle to effectively capture the nonlinear relationships between limited phenotypic data and high-dimensional genotypic data. Deep learning (DL) provided a powerful solution for addressing nonlinear problems. Herein, we proposed a novel deep learning method, named residual attention genomic prediction (ReaGP), which was characterized by two main features. It employed residual units to mitigate gradient instability and network degradation issues, while leveraging attention mechanisms to enhance the mining of critical feature information. Moreover, genomic data processed with frequency encoding was integrated into ReaGP to achieve a richer feature representation. RESULTS:When assessing the predictive accuracy across three animal datasets and two plant datasets covering 15 traits with varying heritabilities, ReaGP improved predictive performance by 14.41% and 7.78% over linear models specifically genomic best linear unbiased prediction (GBLUP) and BayesB, and by 34.41% and 10.09% over kernel methods namely support vector regression (SVR) and reproducing kernel Hilbert space (RKHS), respectively. ReaGP achieved a 4.35% enhancement on average compared to deep neural network genomic prediction (DNNGP). Furthermore, while ReaGP has more trainable parameters than DNNGP, it requires only half the number of floating-point operations. CONCLUSIONS:We introduced a novel deep learning method for genomic prediction, which integrates residual units, attention mechanisms and frequency-encoded genomic data. Comprehensive evaluation on pig, dairy cow, Huaxi cattle, wheat and rice datasets demonstrated that ReaGP was a promising tool for most traits. Thus, ReaGP could be considered as an efficient deep learning method for genomic prediction in farm animals and crops. The source code in this study is available at https://github.com/LiJing5467/ReaGP .

BACKGROUND:Colorectal cancer (CRC) is associated with a high mortality rate. Previous studies have shown that FOXQ1, MMP11, and CST1 play significant roles in various cancers, influencing the invasion and metastasis of tumors. However, their effects on colorectal cancer have not been fully investigated. The purpose of this research was to examine the expression of FOXQ1, MMP11, and CST1 in colorectal cancer (CRC) and to systematically as-sess how these factors relate to clinicopathological characteristics and patient survival outcomes. METHODS:This study retrospectively gathered paraffin-embedded samples from 110 CRC patients who underwent surgery between 2017 and 2018. Meanwhile, relevant data were obtained from public databases to analyze expression differences of FOXQ1, MMP11, and CST1 between tumor tissues and normal lung tissues. We examined the expression of FOXQ1, MMP11, and CST1 using immunohistochemistry. Furthermore, the associations among FOXQ1, MMP11, CST1, clinical-pathological parameters, and prognosis were systematically analyzed. Further verification of the in vitro results was conducted through qRT-PCR. RESULTS:Expression of FOXQ1, MMP11, and CST1 in patients was high, with 83.6%, 67%, and 74.5%, respectively. Through rigorous quantitative analysis of clinical-pathological parameters, the study confirmed that these biomarkers have a close and clinically significant correlation with the progression of TNM staging and the occurrence of lymph node metastasis (p < 0.05). Bioinformatics analysis and qRT-PCR verification both indicated that the expression levels of FOXQ1, MMP11, and CST1 in colorectal cancer (CRC) tissues were significantly higher than those in adjacent non-cancerous tissues. CONCLUSIONS:The research data indicate that the abnormal overexpression of FOXQ1, MMP11, and CST1 in CRC tissues is significantly correlated with poor clinical prognosis in patients. There may be a synergistic effect influencing the invasion and metastasis of tumor cells, positioning them as potential novel therapeutic targets for patients with CRC.

Abstract Limited intratumoral persistence and insufficient proliferative capacity severely restrict the efficacy of chimeric antigen receptor (CAR) T-cell therapies in solid tumors. In this study, we demonstrated that DLL3-targeting CAR T cells co-expressing a CD56 chimeric switch receptor and incorporating parallel 4-1BB costimulatory signaling (DBBζ.CBB) effectively address these limitations. In preclinical small cell lung cancer models, DBBζ.CBB exhibited sustained tumor infiltration, prolonged persistence, and superior antitumor activity. Mechanistically, parallel 4-1BB signaling dynamically programmed CAR T-cell fate by promoting early expansion and memory maintenance, driving a highly proliferative effector state at the intermediate stage, and delaying terminal exhaustion at the later stage, thereby sustaining in vivo persistence and enabling durable antitumor responses. Building upon the intratumoral T-cell pool established by DBBζ.CBB, subsequent DLL3 trispecific T-cell engager administration synergistically enhanced tumor eradication by further boosting CD8+ T-cell infiltration and overall activation while mitigating exhaustion and terminal differentiation. Collectively, these findings establish a clinically translatable combinatorial framework to enhance the efficacy and durability of CAR T therapy in solid tumors. Significance: Incorporation of parallel 4-1BB signaling enhances the persistence and proliferation of DLL3/CD56 CAR T cells and enables effective synergy with DLL3 trispecific T-cell engager for eradication in small cell lung cancer.

Genomic research is currently undergoing a paradigm shift from reliance on a single reference sequence to the use of breed-specific genomes. Chinese indicine cattle (Bos taurus indicus), characterized by their notable tick resistance and heat tolerance, display extensively genetic diversity than taurine. Here, we generated a chromosome level genome assembly of Chinese indicine cattle, achieving a contiguity N50 of 90.92 Mb and an overall size of 2.91 Gb, utilizing PacBio high-fidelity (HiFi) sequencing complemented by Hi-C sequencing technology. The assembly is characterized by near-complete chromosomes, telomeres, and less gaps. Utilizing this highly quality assembly, we explored the phylogenetic relationship and speciation time. The gene family and selection signatures analyses indicated that candidate genes and biosynthetic pathways potentially contributing to disease immunity and thermotolerance of indicine cattle. Altogether, this study enriches the bovine pangenome repository and advances our understanding of the complex evolutionary patterns and distinctive adaptation traits of Chinese indicine cattle.

Lung cancer is the leading cause of cancer-related deaths worldwide. Over the past decade, immunotherapy, represented by immune checkpoint inhibitors (ICIs) targeting programmed cell death protein-1/programmed cell death protein ligand-1 (PD-1/PD-L1) or cytotoxic T lymphocyte associated antigen-4 (CTLA-4), has revolutionized the treatment paradigm of lung cancer, reducing the risk of death by approximately 30%. However, approximately 70% of patients with advanced non-small cell lung cancer are either non-responsive to ICIs or initially respond to treatment but eventually experience disease progression due to acquired resistance. This subset of non-responsive or ultimately resistant patients is often characterized by complete exhaustion of endogenous anti-tumor T cells, which are unable to exert anti-tumor effects, thereby leading to ICI non-response or resistance. Correspondingly, the adoptive transfer of immune cells has shown promising efficacy in numerous clinical studies involving this patient population. Nevertheless, the Food and Drug Administration (FDA) has not yet approved any cell therapy strategy for lung cancer, primarily because of factors such as the hostile tumor microenvironment and T cell exhaustion. Herein, we summarize the current progress in cell therapy for lung cancer, analyze key challenges, and propose potential solutions.

Anemia is one of the most prevalent systemic complications in patients with cancer, substantially impairing quality of life and limiting the safe administration of cytoreductive therapies. Despite its clinical significance, the mechanisms by which tumors disrupt erythroid homeostasis remain incompletely understood. Here, we identify a previously unrecognized mechanism by which tumor-derived DNA directly drives cancer-associated anemia through pathological interaction with circulating red blood cells (RBCs). Specifically, we show that circulating tumor-derived DNA binds to lon peptidase 1 (LONP1), a mitochondrial protease aberrantly expressed on the surface of peripheral blood reticulocytes in tumor-bearing hosts. This interaction induces morphological alterations and apoptosis in reticulocytes, thereby triggering their premature clearance via erythrophagocytosis and contributing to anemia progression. Therapeutically, the enzymatic degradation of surface-bound DNA using Deoxyribonuclease I (DNase I) restores reticulocyte morphology, diminishes erythrophagocytic clearance, and alleviates anemia in tumor-bearing models. Moreover, combining DNase I with erythropoietin-driven stimulation of erythropoiesis produces synergistic hematologic improvement, simultaneously limiting pathological RBC clearance and enhancing RBC production. Together, these findings reveal a previously unappreciated DNA-mediated axis linking tumor burden to systemic erythroid dysfunction. This work establishes circulating tumor-derived DNA as an active pathogenic mediator in cancer-associated anemia and provides a mechanistically grounded combinatorial therapeutic strategy targeting both erythrocyte destruction and impaired erythropoiesis.

Background: From 2019 July 15 to 2022 February 14, the REZOR study enrolled 369 treatment-naïve patients with locally advanced or metastatic non-small cell lung cancer harboring EGFR mutations (exon 19 deletion or L858R mutation). Patients were randomly assigned 1:1 to receive either rezivertinib (180 mg/d) plus gefitinib placebo or gefitinib (250 mg/d) plus rezivertinib placebo. Previous results demonstrated significantly improved progression-free survival (PFS) with rezivertinib versus gefitinib and a favorable safety profile. Here, we update the analyses of central nervous system (CNS) outcomes in patients with baseline CNS metastases. Methods: All patients underwent brain magnetic resonance imaging at baseline and each subsequent efficacy evaluation until radiological disease progression or any other treatment discontinuation criteria were met. EGFR mutation status was determined by testing using tissue or plasma samples during screening. Patients with stable, asymptomatic CNS metastasis were eligible for enrollment. The CNS full analysis set (cFAS) comprised patients with baseline CNS metastasis identified on magnetic resonance imaging and evaluated by blinded independent central review according to the Response Assessment in Neuro-Oncology Brain Metastases criteria. Patients with measurable CNS target lesions formed the CNS evaluable-for-response set (cEFR). Results: As of the 2023 November 30 data cutoff, 159 patients had baseline CNS metastasis in the cFAS (rezivertinib: n = 81; gefitinib: n = 78) and 25 in the cEFR (rezivertinib: n = 12; gefitinib: n = 13) per blinded independent central review. In the cFAS, 59 CNS PFS events occurred (rezivertinib: n = 30; gefitinib: n = 29). Median CNS PFS was significantly longer with rezivertinib (24.9 months; 95% confidence interval [CI], 16.5 months-not estimable [NE]) than with gefitinib (15.2 months; 95% CI, 10.5 months-NE), with a hazard ratio of 0.58 (95% CI, 0.34 to 0.99; P = 0.047). In the cEFR, the CNS objective response rate was 83.3% (95% CI, 51.6% to 97.9%) with rezivertinib and 76.9% (95% CI, 46.2% to 95.0%) with gefitinib (odds ratio = 1.50; 95% CI, 0.20 to 11.0; P = 0.690). No new safety findings were observed. Conclusions: Rezivertinib demonstrated a statistically significant superior CNS efficacy over gefitinib as first-line treatment in advanced EGFR-mutated non-small cell lung cancer patients with baseline CNS metastases. The safety profile was consistent with previous analyses. Trial registration: NCT03866499 (ClinicalTrials.gov).

BackgroundChemotherapy resistance, particularly resistance to oxaliplatin, remains a major clinical challenge in the treatment of colorectal cancer (CRC). Ferroptosis, a newly characterized form of regulated cell death, has emerged as a potential mechanism for overcoming chemotherapy resistance. The transcription factor FOSL1 has been implicated in CRC progression and chemoresistance; however, its role in ferroptosis is not well defined.MethodsGene and protein expression levels were assessed by quantitative real-time PCR (qRT-PCR) and western blotting, respectively. Malondialdehyde (MDA), glutathione (GSH), and intracellular iron levels were measured using ELISA. Lipid peroxidation was evaluated using the C11-BODIPY 581/591 probe. Cell viability and cell death were determined by the CCK-8 assay and Calcein-AM/propidium iodide (PI) double staining, respectively. The interaction between FOSL1 and the SRSF2 promoter was examined using dual-luciferase reporter and chromatin immunoprecipitation (ChIP) assays.ResultsFOSL1 was significantly overexpressed in CRC tissues and oxaliplatin-resistant CRC cells and was negatively correlated with the ferroptosis-related proteins GPX4, SLC7A11, and FTH1. Silencing of FOSL1 reduced oxaliplatin resistance in CRC cells by promoting ferroptosis. Mechanistically, FOSL1 transcriptionally activated SRSF2 expression. Overexpression of SRSF2 reversed the ferroptosis-promoting and oxaliplatin resistance-suppressing effects induced by FOSL1 knockdown.ConclusionFOSL1 promotes oxaliplatin resistance in CRC by suppressing ferroptosis through the upregulation of SRSF2. Targeting FOSL1 may represent a novel therapeutic strategy to overcome oxaliplatin resistance in colorectal cancer.

Aberrant metabolism is a hallmark of tumours. Cancer cells develop metabolic patterns distinct from those of normal cells, characterized by the conversion of glucose into lactate under both aerobic and hypoxic conditions. The intermediates and end products generated in this process modulate the function and survival of immune cells within the tumour microenvironment (TME). In this review, we summarize recent advances in the interplay between glycolysis and the immune microenvironment, potential therapeutic targets within the glycolytic pathway, and the clinical translation of glycolysis-related molecules. Through in-depth research into the glycolytic process, it has been found that the aberrant glycolytic metabolism of tumor cells not only supports their own proliferation but also reshapes the tumor microenvironment. This, in turn, forces immune cells to alter their metabolic profiles, ultimately resulting in an imbalanced anti-tumor immune response. To date, multiple small-molecule inhibitors targeting key molecules and nodes in the glycolytic pathway have been developed, some of which demonstrate promising anti-tumor efficacy in preclinical models. The review emphasizes the significance of glycolysis in shaping the immune response within the TME and underscores the therapeutic potential of targeting glycolytic pathways, with several inhibitors showing promise for future clinical translation.

BACKGROUND:Extensive-stage small cell lung cancer (ES-SCLC) is associated with a high symptom burden and impaired health-related quality of life (HRQoL). This prespecified analysis from the phase 3 DeLLphi-304 trial evaluated patient-reported outcomes (PROs) for tarlatamab versus standard-of-care (SoC) chemotherapy following first-line platinum-based therapy. METHODS:DeLLphi-304 is a multicenter, open-label, randomized phase 3 study in adults with ES-SCLC. PROs were assessed using validated instruments, including the EORTC QLQ-C30, EORTC QLQ-LC13, FACT-G GP5, BPI-SF, and the EQ-5D-5L visual analogue scale. Change from baseline, response rates, and time to deterioration in these PROs were analyzed. RESULTS:PRO data from all 509 patients enrolled were evaluated. Compliance with QLQ-C30 and QLQ-LC13 assessments remained above 69% through 19 weeks. A higher proportion of patients receiving tarlatamab achieved symptom or functional improvement at 19 weeks compared with SoC in chest pain (19% vs 10%), cough (35% vs 26%), dyspnea (22% vs 7%), physical functioning (13% vs 8%), and global health status (23% vs 15%), respectively. Tarlatamab also delayed deterioration in symptoms, physical functioning, and pain at worst relative to SoC. FACT-G GP5 results indicated that patients receiving tarlatamab were less bothered by treatment side effects over time. CONCLUSIONS:In addition to its previously reported antitumor activity, tarlatamab demonstrated clinically meaningful improvements in symptoms and HRQoL compared with SoC. These findings support a favorable benefit-risk profile of tarlatamab in patients previously treated for ES-SCLC.

Integrative use of multi-omics data can enhance genomic prediction, yet its application remains challenged by the high cost, temporal specificity, and instability of transcriptomic signals across developmental stages. To address these limitations, it is crucial to utilize small, high-quality multi-omics datasets to efficiently identify stable, major-effect SNPs that can be applied to larger populations with genomic data alone. We propose AbGP (Attention-based Genomic Prediction), a framework designed to extract these robust genomic features. Using a discovery population of Huaxi cattle (HX_A, n = 218) with matched genotype and transcriptome data, AbGP employed a self-attention mechanism to identify a compact, high-value subset of SNPs (top 1.25

Background: Following the 2021 first International Consensus on Severe Lung Cancer, global attention to patients with PS 2-4 has grown significantly. Recent advances in novel therapies, interventional techniques, and supportive care, along with emerging real world data, have expanded treatment opportunities for this population. To incorporate these advances, we have updated the consensus. Methods: A multidisciplinary panel comprising experts from oncology, radiation oncology, thoracic surgery, radiology, interventional medicine, respiratory medicine, critical care medicine, and nursing. After being presented with a comprehensive review of the current evidence pertaining to severe lung cancer and thorough discussions, the panel reached a consensus on 11 recommendations, each with over 70% expert agreement. Results: The 11 consensus points focused on definition and causes (n=2), assessment and general strategies (n=4), and specific treatment modalities (n=5) were updated or newly developed. This updated consensus emphasizes dynamic and precise detection, robust life support, flexible application of novel therapies, and MDT guided treatment adjustment based on PS dynamics. Early rehabilitation and comprehensive supportive care are integral to disease management. Conclusions: This consensus updates the definition, diagnostic evaluation, and treatment strategies, providing a practical framework for clinicians based on current evidence and multidisciplinary expert consensus. Prospective trials focusing specifically on patients with severe lung cancer are urgently needed.

Tumour-associated macrophages (TAMs) contribute to immune checkpoint blockade resistance, but their impact on intratumoural CD8⁺ T cell distribution remains unclear. Here we show that the expression of the glucose transporter SLC2A1 is spatially negatively correlated with CD8⁺ T cell distribution in both non-small-cell lung cancer (NSCLC) biopsies and murine tumour models. Tumour cell-specific Slc2a1 knockdown fails to reproduce the therapeutic benefit of SLC2A1 inhibition, whereas TAM-specific deletion of Slc2a1 suppresses tumour growth by enhancing the spatial homogeneity and effector function of intratumoural CD8⁺ T cells, thereby improving αPD-L1 efficacy. Spatial profiling of NSCLC specimens further revealed that SLC2A1⁺ TAM-enriched regions exhibit reduced CD8⁺ T cell density, and spatial proximity between these populations predicts resistance to αPD-(L)1 therapy. These findings identify SLC2A1⁺ TAMs as drivers of spatial CD8⁺ T cell exclusion and highlight TAM-specific SLC2A1 as a therapeutic target to overcome immune checkpoint blockade resistance in NSCLC. Wang, Chu, Chen, Wei and colleagues discover a subset of tumour-associated macrophages expressing SLC2A1 whose spatial proximity to CD8+ T cells drives resistance to anti-PD-L1 treatment in non-small-cell lung cancer.

Tumor evolution involves genetic, transcriptional, and phenotypic alterations that shape cancer cell behavior and interactions with the microenvironment. While single-cell technologies have advanced our understanding of this process, spatial dynamics remain incompletely characterized. Here, whole-exome sequencing (WES), imaging mass cytometry (IMC), and spatial transcriptomics (ST) were integrated to study molecular evolution and immune responses in two lung adenocarcinoma (LUAD) mouse models: a genetically engineered model (129S4/Sv-Kras LSL-G12D , termed 129S4 K) and a carcinogen-induced precancer model (129S4 U). Compared to 129S4 K, 129S4 U tumors exhibited higher mutational, neoantigen but lower copy number variation (CNV) burdens at matched developmental timepoints, consistent with findings of higher mutational burden in human smoking-related LUAD than nonsmoking LUAD. We profiled over 1.4 million spatial single cells from 284 IMC regions of interest and 51,531 spatial transcriptomic spots from 156 lesions across 141 mice. Macrophage abundance increased with tumor progression, while CD8 T-cell and B-cell densities declined in late-stage LUAD. 129S4 U showed greater immune infiltration in both tumor and adjacent normal tissue, higher T-cell cytotoxicity signature score in line with its higher mutational and neoantigen burdens. LUAD progression was marked by early morphological shifts and late-stage changes in cell states and interactions. These data define spatial and genetic landscapes of LUAD development and provide a framework for investigating immune evolution and therapeutic strategies in early carcinogenesis.