In this review, we highlight that MTC is consistently driven by a small number of specific pathogenic variants

The gap

Evidence profile

Sourced from the future work of the source papers, classified as general, drawn from work published between 2024 and 2026, spanning 3 journals. Those papers have been cited 20 times in total.

Supporting evidence — 3 representative gaps

• Cancer drug response and resistance: molecular mechanisms and combating strategies (2026) · Signal Transduction and Targeted Therapy · cited 1× · doi

  Therapeutic resistance remains one of the major obstacles in cancer treatment, limiting the long-term efficacy of standard and targeted therapies.1 As summarized in this review, resistance is not solely dictated by tumor-intrinsic genetic alterations but is shaped by a dynamic interplay among clonal evolution, signaling rewiring, epigenetic remodeling, altered DNA damage repair, metabolic adaptation, dysregulated cell death, TCP, microenvironmental remodeling, and host–microbe–tumor interactions. Tumor hetero- geneity is a fundamental hallmark of cancer and a central driver of this process.9 The diversity of the genetic, transcriptomic, epigenetic, and phenotypic levels gives rise to intratumoral heterogeneity, which underlies the wide variability in treatment responses. Acquired resistance often originates from preexisting heterogeneity within the tumor and is further shaped by continuous diversification during therapy, enabling certain subclones to survive therapeutic pressure and eventually emerge as dominate resistant phenotypes.461 Primary early-stage tumors and advanced metastatic lesions also exhibit marked differences in tumor heterogeneity, drug resistance, and TME composi- tion.399,462 A pancancer whole-genome sequencing (WGS) study revealed that metastatic tumors frequently evolve from dominant subclones in the primary lesion, displaying higher clonality and lower intratumoral heterogeneity.463 These observations under- score the need to understand resistance not as a single molecular event but as an evolving, systems-level property of cancer. and microenvironmental Beyond genetic diversity, accumulating evidence indicates that therapeutic resistance is increasingly driven by non-genetic adaptive processes. Phenotypic plasticity, including EMT, lineage switching, CSC reprogramming, and DTP states, enables tumor cells to survive therapeutic pressure in the absence of stable genetic alterations.308,309 These transient adaptive states may subsequently serve as reservoirs from which genetically resistant clones emerge. Importantly, such plasticity is tightly regulated by epigenetic remodeling, metabolic adaptation, stress-response programs, cues, highlighting the dynamic and reversible nature of resistance.308,316 To address this evolutionary challenge, ecology- and evolution-informed treat- ment paradigms have been proposed. For example, adaptive therapy dynamically adjusts drug dosing to maintain a population of drug-sensitive cells, thereby constraining the competitive expansion of resistant clones.461 These model-driven, personalized dosing strategies aim to match the evolving tumor landscape in real time. Future therapeutic strategies should therefore move beyond targeting individual mutations and instead focus on disrupting the adaptive networks that sustain tumor evolution, cellular state transitions, and minimal residual disease. Another major challenge lies in the increasing recognition that resistance is not solely a tumor cell–intrinsic phenomenon. CAFs, TAMs, MDSCs, exhausted T cells, extracellular matrix remodeling, and microbial communities collectively shape a permissive ecosystem that protects tumor cells from therapeutic eradica- tion.135,136 The TME promotes resistance by restricting drug penetration, suppressing antitumor immunity, providing survival cytokines, maintaining CSC niches, and reinforcing immune- excluded or immune-cold states.123,135 Similarly, the intratumoral and gut microbiome can modulate therapeutic outcomes by altering drug metabolism, reshaping host immunity, producing and activating oncogenic immunomodulatory metabolites,

  generalfuture work
  Keywords: tumor resistance therapeutic genetic drug remodeling heterogeneity adaptive cells cancer evolution epigenetic intratumoral resistant states
• The impact of p53 mutation on tumor immune evasion: mechanistic insights and clinical implications (2026) · Frontiers in Immunology · cited 11× · doi

  Mtp53 is not merely a loss-of-function variant but an active “systemic rewirer” that drives tumor progression and immune evasion through GOF activities. This review has outlined how Mtp53 establishes a highly coordinated oncogenic network via the metabolism–epigenetics–immunity axis. From aberrant LLPS leading to pathological nuclear condensates, to metabolic rewiring—lactate accumulation, a-KG imbalance, and acetyl-CoA enrichment—acting as epigenetic messengers that reshape chromatin landscapes, and further to multilayered immunosuppression including T-cell exhaustion, NK cell inhibition, TAM/M2 polarization, and CAF activation, Mtp53 orchestrates a pro-tumorigenic ecosystem through both cell-autonomous and non-autonomous mechanisms. This multidimensional regulatory network explains its strong association with poor prognosis and resistance to immunotherapy, underscoring Mtp53’s role as a central signaling hub in cancer. However, Mtp53 function exhibits marked mutation dependency, tissue specificity, and dynamic evolution, resulting in heterogeneous— sometimes contradictory—effects on the TIME. For instance, TP53/ KRAS co-mutated lung cancers may respond to ICB, whereas TP53 mutations in triple-negative breast or colorectal cancers are often linked to “cold” tumor phenotypes. Notably, in specific genomic contexts such as TP53/KRAS co-mutated NSCLC, Mtp53 is associated with high tumor mutational burden and neoantigen load and paradoxically correlates with enhanced immune infiltration and improved response to immune checkpoint blockade (ICB), reflecting its potential immunogenic role. This context dependence challenges the utility of TP53 mutation status as a standalone biomarker and underscores the need to move beyond binary “mutant vs. wild-type” classification toward a multidimensional, spatiotemporally resolved understanding of Mtp53 biology. Future breakthroughs will require synergistic advances across several fronts. First, targeting the biophysical behavior of Mtp53— particularly its enhanced LLPS capacity—could open a new therapeutic paradigm. Pathological nuclear condensates formed by Mtp53 can sequester transcriptional co-activators (e.g., BRD4, Mediator), driving immunosuppressive gene programs. Developing small molecules, peptide mimetics, or molecular glues that selectively disrupt these condensates, combined with cryo-EM structural insights, single-molecule imaging, and AI-driven drug design, may enable precise reversal of oncogenic transcription. Second, building integrative biomarker platforms is essential for precision targeting. Genomic profiling alone is insufficient. A dynamic framework integrating mutation conformation classes (e.g., R175H, Y220C), single-cell and spatial multi-omics of the TIME, and ctDNA-based monitoring of clonal evolution is urgently needed. Such platforms could enable patient stratification and real- time detection of adaptive resistance, guiding optimal timing and selection of combination therapies. Third, mutation-informed combination strategies are critical. Given the complexity and redundancy of the Mtp53 network, monotherapy is unlikely to succeed. Ideal regimens may combine Mtp53 reactivators (e.g., APR-246, PC14586) or degraders (e.g., HDAC6 or MVA pathway inhibitors) with ICB to restore T-cell responses; pair metabolic modulators (e.g., MCT4/GLUT1 inhibitors) or epigenetic drugs (e.g., EZH2/BET inhibitors) to reverse immune gene silencing; and explore Mtp53 neoantigen vaccines or adoptive cell therapies to turn Mtp53 into an immunogenic target. However, the phase III failure of APR-246 in MDS (NCT03745716) was likely due to a lack of stratification by mutation subtype—such as the inclusion of patients with nonsense or frameshift mutations—highlighting the need for future trials to prospectively enrich for populations with conformationally sensitive mutations. Meanwhile, although combinations of Mtp53- targeted agents with metabolic inhibitors or immune checkpoint inhibitors (ICIs) hold therapeutic promise, their cumulative toxicities (e.g., energy deprivation–related organ damage or immune-related adverse events [irAEs]) have not been systematically evaluated in preclinical models. It is therefore urgent to define the therapeutic window and maximum tolerated dose in humanized models to ensure that efficacy gains are not offset by unmanageable toxicity. Finally, distal regulation and niche modulation warrant deeper exploration. Mtp53 communicates with stromal cells (CAFs), myeloid populations, and even the gut microbiota via exosomes, cytokines, and metabolites. These non-tumor components may feed back to stabilize Mtp53 or amplify its GOF. Targeting the tumor niche—through stromal reprogramming, microbiome modulation, or dietary interventions—could enhance therapeutic efficacy and delay resistance.

  generalfuture work
  Keywords: immune cell tumor mutation inhibitors therapeutic network condensates metabolic resistance time mutations cation targeting function
• Medullary Thyroid Cancer: Molecular Drivers and Immune Cellular Milieu of the Tumour Microenvironment—Implications for Systemic Treatment (2024) · Cancers · cited 8× · doi

  In this review, we highlight that MTC is consistently driven by a small number of specific pathogenic variants, beyond which few additional genetic events are required for tumorigenesis. This homogeneity of driver events explains the exceedingly low tumour mutational burden seen in MTC, in contrast to other cancers. However, as a result, there is a correspondingly low level of tumour-associated neoantigens presented to the host immune system. This reduces tumour visibility and the vigour of the anti-tumour immune response. In addition, it suggests the efficacy of immunotherapy in MTC is likely to be poor, acknowledging this inference is largely based on the extrapolation of data from other tumour types. Specific to MTC, the immune microenvironment has not been extensively described, with conflicting data published to date. Correlation of the cytokine and immune cell profile of the TME with the underlying molecular subtype, clinicopathological factors and prognosis, as well as description of changes that occur in the TME with TKI therapy remain important areas for future research. The dominance of specific RET pathogenic variants in MTC tumorigenesis rationalises the observed superior efficacy of the targeted RET TKIs in comparison to MKIs. Therapeutic durability of RET-specific pathway inhibitors is also superior to that of the MKIs; however, the development of resistance to pathway inhibition remains an inherent limitation of TKI treatment. Resistance may develop through the selection pressure TKI treatment creates, promoting survival of resistant tumour cell clones that can escape pathway inhibition through binding-site mutations, activation of alternate pathways, and modulation of the cellular and cytokine milieu of the TME. The optimal therapeutic strategies to delay the emergency of resistance and the approach to management once resistance occurs remain important areas for future research. Author Contributions: Conceptualization, A.J.P. and S.B.S.; methodology, A.J.P., H.S.-B., A.J.P. and H.S.-B.—original draft preparation, A.J.P.; writing—review and editing, A.J.P., R.C.-B., A.J.G. and S.B.S.; supervision, S.B.S. All authors have read and agreed to the published version of the manuscript. Funding: This research received no external funding. Institutional Review Board Statement: Not applicable. Informed Consent Statement: Not applicable. Data Availability Statement: Not applicable. Conflicts of Interest: The authors declare no conflicts of interest. Cancers 2024, 16, 2296

  generalfuture work
  Keywords: tumour specific immune resistance review pathway statement applicable pathogenic variants events tumorigenesis cancers efficacy published

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