TMB-H

Prospective studies and registry-based analyses are needed to refine risk assessment, optimize management, and maximize the clinical utility of POLE profiling. This review provides a comprehensive and integrative overview of POLE alterations across human cancers, integrating molecular, clinicopathological, and immunological insights with therapeutic implications.

Given the challenges in diagnosis and the potential for rapid recurrence or metastasis, early detection is crucial. Comprehensive genomic profiling is highly desirable, as genomic analysis may direct the development of targeted therapeutic agents to treat relapse.

APOBEC mutational signatures represent a robust predictive biomarker for ICI response in TMB-low metastatic NSCLC, identifying responders particularly among PD-L1-negative patients where biomarker guidance is most needed, detectable from targeted gene panels used in routine clinical practice.

This study reveals the unique molecular landscape of EBV+ IFDCS, characterized by frequent NQO1 mutations and activation of key oncogenic pathways. These findings provide critical insights into the tumor's pathogenesis and suggest potential molecular targets for future therapeutic strategies.

This has changed the treatment landscape of this small subgroup of metastatic CRC (mCRC), including the approval of pembrolizumab as a first-line option...Therefore, current approaches aim to convert these "cold" tumors into "hot," immunologically active tumors. This review summarizes the distinct molecular basis of MSI phenotypes and their interaction with the tumor microenvironment, and provides relevant insights into current clinical evidence for prognostic and predictive biomarkers beyond MSI status, as well as novel therapeutic strategies to overcome resistance in MSS disease.

Despite advances with anti-PD-1 therapies, such as nivolumab and pembrolizumab, many patients still experience resistance. Integration of PD-1 and CD73 pathways suggests that CD73 inhibition may enhance PD-1 blockade by targeting convergent immunosuppressive mechanisms. This supports the exploration of combination strategies to broaden the benefits of immunotherapy in CM.

Forced upregulation of IRGs in ADAR1-deficient cancer cells restored immunotherapy responses during microbial ablation. These data highlight dynamic interplay between ITMB, host defense, and immunogenicity which seems key to determine therapy responses.

Here, we report a patient with locally advanced Gleason 5 + 5 = 10 prostatic adenocarcinoma harboring MSH2 and MSH6 genomic deletions with ultrahigh TMB (>250 mutations/megabase) in whom pembrolizumab resulted in a striking complete radiographic, pathologic, and molecular response...Similar T cells are also present in diverse cancers and expand exclusively in ICI-responsive patients. These findings inform on the cellular mechanisms by which immunotherapies may mediate profound responses in patients with dMMR solid tumors.

These observed frequencies should be interpreted as case-level implementation signals surfaced through routine CGP rather than assay superiority evidence, biological prevalence estimates, or treatment-benefit data. This nationwide, platform-aware benchmark supports practical interpretation of tumor-agnostic eligibility signals in routine CGP practice in Japan.

These findings provide proof-of-concept that site-directed RNA editing can be used to reprogram tumor immunogenicity by generating defined neoantigen-like epitopes from shared tumor-associated antigens. This strategy may expand neoantigen-based immunotherapy beyond tumors with high mutational burden and warrants further investigation for clinical translation.

This retrospective, single-center cohort study used the Research Patient Data Registry (RPDR) to identify adults with breast cancer, lung cancer, renal cell carcinoma, or melanoma who received PD-1 inhibitor monotherapy (pembrolizumab or nivolumab) between January 1, 2000, and May 29, 2024. Higher TMB and enrichment of selected tumor mutations may reflect a tumor immunogenicity state that predisposes to pituitary autoimmunity under PD-1 blockade. These findings provide a hypothesis-generating genomic framework for future studies of endocrine irAE risk stratification.