A growing mismatch has emerged between the promises of precision medicine in oncology, and the real-world outcomes observed across Cancer, associated cardiovascular diseases, and complex (CO-)morbidities in the POSTCOVID-19 era. Recent global datasets reveal persistent, accelerated, and excessive mortality since 2020, with monthly death rates exceeding pre-pandemic baselines by 20–40% in several regions. These trends coincide with rising (CO-)morbidities among an estimated 400–600 million long-COVID patients, increasing treatment-related injuries, and stagnation in long-term cancer survival despite three decades of technological innovation. The central question remains unresolved; which this commentary focused on is: why can one patient reverse autoimmune or malignant progression while another cannot? Different hypothetical aspects suggest that the existence of mechanistic determinants—potentially certain protein-protein interaction (manipulations), and having strong cellular systems, or regulatory networks with definable half-times of efficacy—might help clinicians to recall their old-fashioned treatments, totally. On the other hand, by governing therapeutic windows, resilience, and inducing biological reversibility, many cancer patients survive the first decade, after primary diagnosis. Although modern therapeutics are marketed as “precise,” clinical evidence demonstrates that targeted drugs still disrupt normal pathways, immunotherapies induce chronic systemic toxicities, and advanced radiotherapy platforms inevitably damage surrounding tissues. These contradictions highlight a structural problem which is discussed here, by recalling precision tools that have been advanced or not, while precision biology still has not. Legacy diagnostics, outdated prognostic models, and bias-based treatment algorithms continue to shape Medicare and Medicaid pathways, failing to incorporate mechanistic insights, long-term toxicity data, or POSTCOVID-19 epidemiological realities, should be revised (or not). The persistence of preventable mortality—especially among children with biologically curable diseases—underscores systemic failures: late detection, rigid algorithms, selective high-cost therapies with marginal benefit, and subsidized research pipelines that do not yield proportional survival gains. As global cancer mortality continues to rise, and mortality-to-incidence ratios remain high even in high-income countries, a transparent, mechanistic reframing of medical precision is urgently required. This commentary argues that the next era of diagnostics and prognostics must integrate mechanistic biology, real-world toxicity, long-term outcomes, and unbiased epidemiological data. Only through such recalibration can precision medicine evolve from a marketing narrative into a scientifically grounded, patient-relevant framework.

COVID-19, Oncology, Cancer, Precision medicine