Immune checkpoint inhibitors (ICIs) have transformed cancer therapy, yet the basis of variable patient responses remains unclear. We assemble a longitudinal single-cell RNA sequencing atlas of 441 samples from 241 patients across ten cancer entities to map treatment-associated remodeling of the tumor immune microenvironment (TIME). With a hierarchical reference-guided deep-phenotyping framework, we define 77 immune and stromal subtypes and resolve four conserved TIME subtypes. Approximately 40% of tumors shift between states during therapy, and the transition is more predictive of outcome than the baseline state. Favorable transitions toward inflamed or B cell-enriched subtype track with improved response and survival, while persistence in or shifts toward myeloid dominance indicate resistance. We derive a 59-gene signature that predicted response and survival for 1,383 baseline tumors across 19 independent cohorts. These findings establish immunotype transitions as a central determinant of ICI efficacy, offering new avenues for response prediction and rational immunotherapy design.

We performed an integrated clinical and genomic analysis of over 7,000 consecutively sequenced colorectal cancer (CRC) samples to comprehensively characterize genetic drivers and metastatic tropisms of CRC. We find that genomic evolutionary changes, such as clonal mutations and oncogenic mutant allelic imbalance, selectively enhance the impact of recurrent oncogenic alterations. We identify the relative timing of organ-specific metastasis, showing sequential metastatic progression in microsatellite stable CRC with brain and adrenal metastases as late events; metastatic sites that cluster together, such as lung, bone, and brain metastases; and genomic events that enhance or decrease risk for each metastatic site, with WNT pathway activation as overall protective while RAS pathway activation increased risk for spread to all metastatic sites. Our data suggest that despite the heterogeneity in CRC, genomic evolution increases the impact of recurrent alterations, and integrating information about tumor primary location and genomics can be used to predict organ-specific metastasis risk.

In this issue of Cancer Cell, Manca et al. investigate the genomic evolution and metastatic tropism of over 7,000 colorectal cancers. Integrating primary tumor location, genomic alterations, and clinical variables, they reveal how distinct patterns of tumor evolution shape metastatic competence and impact organ tropism, offering a framework to refine surveillance.

Biomarkers for immune checkpoint inhibitors have largely treated the tumor immune microenvironment as a fixed property. In this issue of Cancer Cell, Lin et al. assemble a longitudinal pan-cancer single-cell atlas and show that the direction of immune-state remodeling during therapy is more informative than baseline composition.

Cancer genomes harbor hundreds of mutated genes, but their exact roles in tumorigenesis often remain incompletely understood. Here, by integrating protein structures with mutation data from 139,818 patients, we generate detailed, functional maps of mutations for 173 cancer genes in 18+ tumor types. In most cancer genes, oncogenic mutations accumulate in "significantly mutated regions" aligned with key functions, including DNA-binding domains in transcription factors (e.g., FOXA1), ligand-binding sites in receptors (e.g., ERBB2), catalytic domains in chromatin remodelers (e.g., EP300), substrate-recognition sites in ubiquitin-proteasome regulators (e.g., SPOP), and degradation signals in cell-cycle proteins (e.g., CCND1). In other cancer genes, mutations align more closely with constraints in three-dimensional protein structures, such as targeting the interior core (e.g., TP53) or a specific secondary structure (e.g., PTEN). Broadly, our study provides a proteo-genomic framework to characterize the effects of mutations in tumorigenesis and integrate them into workflows for clinical interpretation in precision medicine.

In Cell Press Blue, Carvalho et al. identify spatially organized tumor-macrophage niches, EMT-like CD44[high] cancer cells paired with SPP1/PARP14[high] macrophages, that drive chemoresistance in bladder cancer. PARP14 inhibition can flip this protective niche into an inflammatory, cisplatin-sensitizing state.

In a Nature Medicine study, Tian et al. identify larger biological age gaps associated with early-onset lung, colorectal, and uterine cancers across birth cohorts. These findings position biological age as an integrative marker of physiological dysregulation. Future work combining aging clocks and mutational signatures could distinguish tumor-promoting states from tumor-initiating exposures.

Tertiary lymphoid structures (TLSs) drive antitumor immunity, but their functional heterogeneity translates into inconsistent immunotherapy responses in hepatocellular carcinoma (HCC), raising the question of which immune niches actually predict efficacy. Using spatial multi-omics analysis, we uncover a distinct niche, the stem-like lymphoid niches (SLNs), that correlates with stronger responses to PD-1/PD-L1 blockade. Unlike conventional TLS, SLNs feature a specialized niche of CD70[+] type 2 innate lymphoid cells (ILC2s) and progenitor exhausted T (Tpex) cells. Intriguingly, intratumoral Bacillus cereus promotes SLN accumulation via triggering endothelial IL-33 release, which rewires ILC2s metabolism and enhances H3K4me3-mediated epigenetic activation of CD70, Lta, and Ltb genes, reinforcing the niche's lymphoid-organizing function. We identify the bacterial phosphoinositide-specific phospholipase C (PI-PLC) as the effector behind this endothelial IL-33 release. Combining PI-PLC with αPD-L1 synergistically amplifies antitumor immunity, highlighting SLNs as a promising target for boosting immunotherapy in HCC.

In this issue of Cancer Cell, Li et al. report a first-in-human phase 1 study of SYS6010, an epidermal growth factor receptor (EGFR)-targeting antibody-drug conjugate, in advanced solid tumors. The study highlights how EGFR-directed therapy moves beyond kinase inhibition toward antigen-guided cytotoxic delivery in non-small cell lung cancer.

SYS6010 is an antibody-drug conjugate targeting epidermal growth factor receptor (EGFR). We report the results of a phase 1 trial (ChiCTR2300072141) of SYS6010 in patients with non-small cell lung cancer (NSCLC). A total of 236 patients were treated. One dose-limiting toxicity occurred at 6.4 mg/kg; therefore, 4.2, 4.5, and 4.8 mg/kg were selected for cohort expansion. Treatment-related adverse events (TRAEs; any/grade ≥ 3) occurred in 99.6%/57.2% of patients. Common grade ≥3 TRAEs included neutropenia (30.9%), leukopenia (25.0%), and thrombocytopenia (17.4%). Objective response rate was 34.7% in EGFR-mutant NSCLC treated with EGFR tyrosine kinase inhibitors (TKIs) and platinum chemotherapy, 45.7% in EGFR-mutant NSCLC treated with EGFR TKIs, 20.0% in EGFR wild-type squamous NSCLC, and 35.7% in EGFR wild-type non-squamous NSCLC. Median progression-free survival and overall survival were 7.6 and 19.4 months, respectively, in EGFR-mutant NSCLC treated with EGFR TKIs and platinum chemotherapy. Overall, SYS6010 shows a manageable safety profile and encouraging antitumor activity in previously treated, advanced NSCLC.

In this issue of Cancer Cell, Kehl et al. construct a single-cell atlas of bone marrow T cells from patients with bone marrow-resident malignancies, identifying tumor-reactive populations existing in a state of latent competence. A 15-gene signature identifies this subset, which is expanded by immunotherapies and predicts clinical responses.