Srikanth Ponneganti

Poly (ADP-ribose) polymerase inhibitors (PARPi) have transformed the treatment landscape for homologous recombination-deficient (HRD) cancers, particularly those harboring BRCA1/2 mutations, including breast, ovarian, prostate, and pancreatic cancers, by exploiting the synthetic lethality induced by HR deficiency (HRD) and utilizing HRD status as a predictive biomarker. Nevertheless, intrinsic as well as acquired resistance limits their long-term effectiveness. Resistance often develops as a result of several complex mechanisms including the restoration of homologous recombination (HR), stabilization of the replication fork, enhanced drug efflux, loss of PARP1 expression, epigenetic modifications, and changes in the DNA damage response signaling. BRCA1/2-mutant cells, deficient in HR, become reliant on alternative repair pathways like classical non-homologous end joining (c-NHEJ) and microhomology-mediated end joining (MMEJ). Emerging evidence indicates the importance of replication-induced gaps in single-stranded DNA (ssDNA) and alternative pathways of DNA repair in defining PARPi sensitivity and resistance. This review aims to provide a comprehensive analysis of the established and emerging molecular mechanisms of PARPi resistance, and compensatory DNA repair pathways such as MMEJ. In addition to highlighting resistance pathways, the review also discusses strategies focusing on targeting repair mechanisms and replication stress signaling by using novel drugs targeting DNA polymerase theta (POLQ). It subsequently discusses preclinical advancements and ongoing clinical trials. Through linking the molecular determinants of resistance to the translational status and limitations of the latest therapies, this review offers a comparative framework for understanding resistance mechanisms and strategies to restore PARPi sensitivity in cancers with HRD.

Head and neck squamous cell carcinoma (HNSCC) continues to pose a major global health challenge, with over 600,000 new cases diagnosed annually and persistently poor survival outcomes despite advances in surgery, radiotherapy, and immunotherapy. Growing evidence implicates metabolic reprogramming, including enhanced glycolysis, glutaminolysis, lipid synthesis, and one-carbon/redox flux as a central driver of HNC initiation, progression, and therapy resistance. In contrast, metabolic crosstalk within the hypoxic, acidic tumor microenvironment (TME) further shapes immune evasion and stromal support. Recent innovations in mass spectrometry platforms (LC-MS, GC-MS, NMR) have attracted attention in clinical therapeutics, and spatial metabolomics imaging techniques now enable high-resolution in situ mapping of metabolites, revealing intratumoral heterogeneity and offering new insights into tumor-immune–stromal interactions and potential biomarkers for precision oncology. In this review, we integrate critical methodological considerations from sample collection and data-analysis workflows to analytical pitfalls with a balanced, pathway-focused analysis of HNSCC dysmetabolism, examine tumor immune stromal metabolic interactions, and highlight translational opportunities through emerging biomarkers, targeted inhibitors, and cutting-edge approaches such as single-cell and AI-driven metabolomics to chart a roadmap toward precision oncology for HNSCC.