Editorial on the Research Topic Impact of Cancer Plasticity on Drug Resistance and Treatment in Solid Tumors The Research Topic “Impact of Cancer Plasticity on Drug Resistance and Treatment in Solid Tumors” consists of 32 articles contributed by more than 270 authors in the field of oncology, pharmacology, and translational research. Our aim was to provide a collaborative discussion on molecular and cellular regulators of cancer cell plasticity contributing to tumor progression and drug resistance for the future direction of biomarker discovery and therapeutic strategies. Cancer stem cells, tumor microenvironment, stroma/cancer cells interactions, changes in metabolism and epithelial-mesenchymal transition offer explanation for tumor plasticity. The current state of art in this era was elegantly reviewed by Fanelli et al., Yang et al., and Lin X. et al., who discussed the clinical relevance of cancer cell plasticity, the novel approaches for monitoring tumor plasticity and the current advances for therapeutic targeting. Yu et al. found that the FAP-a+GOLPH3+ immunophenotype, combining the expression of both the fibroblast activation protein-alpha and the oncogenic Golgi phosphoprotein 3 protein predict the recurrence and progression of ductal carcinoma in-situ (DCIS) into invasive breast cancer. Yao et al. demonstrated in mouse experiments that the levels of MTA3 and SOX2 decreased and increased, respectively, during the progression of tongue squamous cell cancer (TSCC), and that MTA3low/SOX2high can serve as an independent prognostic factor for TSCC patients. Chen et al. confirmed that overexpression of PD-L1 occurred predominantly in highly aggressive glioma cells, and Akt binding/activation prevented autophagic cytoskeleton collapse, thus facilitating glioma cell invasion upon starvation stress. Sun et al. showed that SIRT5, a mitochondrial class III NAD-dependent deacetylase, contributes to cisplatin resistance in ovarian cancer by suppressing cisplatin-induced DNA damage in a reactive oxygen species (ROS)-dependent manner, via the regulation of the nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase 1 (HO-1) pathway. The study from Tang et al. suggested that the Pigment epithelium-derived factor (PEDF) participates the carcinogenesis of human esophageal squamous cell carcinoma and might be a candidate therapeutic target. Finally, analyses conducted by Zhang J. et al. on single-cell sequencing datasets of several human cancers indicated a tumor suppression function of the ZNF671 transcription factor. Fahs et al. demonstrated that the PAX3-FOXO1 fusion protein modulates exosome cargo to confer a protective effect on recipient cells against oxidative stress and to promote plasticity and survival, potentially contributing to the known aggressive phenotype of the fusion gene-positive subtype of Rhabdomyosarcoma. Guo T. et al. reported a clinical case showing change of pathological type to metaplastic squamous cell carcinoma of the breast during disease recurrence. Epigenetic reprogramming favors cancer plasticity. The discovery of non-coding RNA such as microRNA (miR), Long non-coding RNA (LncRNA) and circular RNA (circ-RNA) is propelling the future advancement of biomarker development and offers opportunities to understand their role in the hallmarks of cancer, including signaling pathways involved in cell proliferation, cell invasion, metabolic plasticity and drug resistance. Wan et al. deciphered the functional domains of the channel-kinase transient receptor potential ion channel subfamily M, member 7 (TRPM7) involved in glioma cell growth or migration/invasion. TRPM7 was found to regulate miR-28-5p expression, which suppresses cell proliferation and invasion in glioma cells by targeting the Rap1b signaling. Guo J. et al. demonstrated that miR-204-3p, whose down-regulation was significantly associated with poor prognosis in bladder cancer patients, negatively modulated the proliferation of bladder cancer cells via targeting the lactate dehydrogenase (LDHA)-mediated glycolysis. Huang et al. elegantly provided evidence that LncRNA AFAP1-S1 up-regulates the RRM2 protein levels by sponging miR-139-5, then activating an RRM2/EGFR/Akt axis that promotes chemoresistance in non-small cell lung cancer. Supportive in vivo experiments further demonstrated that knockdown of AFAP1-AS1 significantly suppressed tumor growth and chemoresistance. Li W. et al. proved that miR-199a, by directly regulating K-RAS and thus the downstream AKT and ERK signaling, inhibits glioma cell proliferation in vitro, tumor growth in vivo and increases sensitivity to telozomide, a drug used in first line treatment of glioma. Lin X.-J. et al. highlighted the role of miR-936 in sensitizing laryngeal squamous cancer cells to doxorubicin and cisplatin. Liu C. et al. experiments suggested that miR-34a-5p, by directly targeting thymidine kinase 1 (TKI), may be part of the mechanisms negatively regulating TKI-driven thyroid carcinoma cell aggressiveness. Growing body of evidence indicate that circRNAs play a role in disease progression, partly by sponging miRNA, and may be used as biomarkers. Gao et al. identified a candidate circRNA associated with poor prognosis in multiple myeloma. Finally, the review by Guo Q. et al. elegantly depicted and discussed the role of exosomal miRNA as a regulators and biomarkers in cancer drug resistance. It is of utmost importance to decipher how chronic exposure to environmental carcinogens contribute to cell plasticity and tumor progression. The identification of such molecular mechanisms may help in the discovery of human biomarkers of environmental carcinogen exposure and the development of candidate preventive strategies. Using an in vitro model for malignant transformation of normal lung cells upon long-term exposure to cigarette smoke, Wang et...