Mechanistic studies should connect tumor-intrinsic

The gap

Evidence profile

Stated in the future work and cells future research sections of the source papers, classified as general, spanning 3 journals.

Supporting evidence — 3 representative gaps

• THE ROLE AND THERAPEUTIC STRATEGIES OF PRECURSOR EXHAUSTED CD8-positive T CELLS IN TUMOR IMMUNITY (2026) · Journal of Pharmaceutical and Medical Research · doi

  As a key subset within the exhaustion differentiation hierarchy, Tpex combine self-renewal capacity with redifferentiation potential and have emerged as a central entry point for understanding durable responses to tumor immunotherapy. Current evidence indicates that the long-term efficacy of immune checkpoint blockade depends less on functional recovery of terminally exhausted cells than on the abundance, differentiation plasticity, and niche support of Tpex. Accordingly, optimization of tumor immunotherapy is shifting from a narrow emphasis on enhancing effector function to a broader strategy aimed at maintaining, expanding, and efficiently mobilizing the precursor pool. At the same time, the formation and maintenance of Tpex are jointly shaped by transcriptional regulation, metabolic adaptation, epigenetic remodeling, and microenvironmental signals, suggesting that no single universal regulatory switch exists. Future strategies with stronger translational potential should therefore respect differentiation hierarchy and therapeutic timing, and should emphasize systematic combination designs centered on Tpex expansion, niche remodeling, and intervention in resistance-associated pathways, rather than focusing only on reversal of terminal Tex. Overall, research on Tpex is moving tumor immunotherapy beyond short-term effector intensity and toward a broader concern with durability, plasticity, and the tissue ecology of immune responses. Continued advances in spatial multi-omics, lineage tracing, and dynamic clinical monitoring are expected to deepen both mechanistic understanding and translational application of Tpex biology, thereby providing a stronger theoretical foundation for precision immunotherapy. COMPETING INTERESTS The authors have no relevant financial or non-financial interests to disclose. REFERENCES Alsaafeen B H, Ali B R, Elkord E. Resistance mechanisms to immune checkpoint inhibitors: updated insights. Molecular cancer, 2025, 24(1): 20. Wang J, Yan R, Jia D, et al. Reprogramming T cell stemness against cancer. Trends in cancer, 2026, 12(1): 68-79. Yu Y, Yao X, Wang Q, et al. T Cell Exhaustion in Cancer Immunotherapy: Heterogeneity, Mechanisms, and Therapeutic Opportunities. Advanced science (Weinheim, Baden-Wurttemberg, Germany), 2026: e20634. Volume 8, Issue 2, Pp 47-55, 2026 54 ShuHua Chen, et al. Lan X, Mi T, Alli S, et al. Antitumor progenitor exhausted CD8(+) T cells are sustained by TCR engagement. Nature immunology, 2024, 25(6): 1046-1058. Tsui C, Kretschmer L, Rapelius S, et al. MYB orchestrates T cell exhaustion and response to checkpoint inhibition. Nature, 2022, 609(7926): 354-360. Gill A L, Wang P H, Lee J, et al. PD-1 blockade increases the self-renewal of stem-like CD8 T cells to compensate for their accelerated differentiation into effectors. Science immunology, 2023, 8(86): eadg0539. Humblin E, Korpas I, Lu J, et al.

  generalstated in future workevidence 5/5
  Keywords: tpex immunotherapy differentiation cancer exhaustion self renewal tumor immune checkpoint cells wang cell hierarchy potential
• Multidrug resistance in cancer: current understandings and future perspective (2026) · Molecular Biomedicine · doi

  The conceptual framework of cancer MDR has defini- tively shifted from a static “drug efflux” model to a dynamic, multidimensional defense ecosystem. As syn- thesized herein, MDR is an emergent property of bidi- rectional tumor-TME crosstalk, integrating cell-intrinsic plasticity (e.g., CSC/DTP dynamics, metabolic-epigenetic rewiring) with extrinsic non-autonomous defenses (e.g., CAF-mediated desmoplasia, immune exclusion). Con- ventional therapeutic failure stems fundamentally from targeting isolated nodes within this network, overlook- ing the functional redundancy that facilitates tumor cell switching between transient adaptive tolerance and fixed genetic resistance along the “resistance continuum.” This dual-layered architecture evolves spatiotempo- rally: temporally via evolutionary subtypes (de novo to cross-resistance) securing clonal selection windows, and spatially through TME-facilitated horizontal propaga- tion of resistance (e.g., TNT-mediated mitochondrial transfer). Crucially, this adaptive reprogramming exposes actionable vulnerabilities. The reliance of DTPs on H4K20me3-mediated epigenetic silencing and the meta- bolic addiction of resistant clones to OXPHOS represent high-value therapeutic targets, necessitating a strategic pivot from “mono-targeted killing” to “multidimensional ecological remodeling.” Future strategies must converge on the integration of predictive and interventional technologies. Leverag- ing artificial intelligence, single-cell multi-omics, and longitudinal liquid biopsies will enable dynamic early- warning networks capable of prospecting resistance tra- jectories. These predictive capabilities must be paired with next-generation interventions—including spati- otemporally controlled nanomedicine, PROTACs, and immunotherapies targeting CSC/DTP-specific antigens (e.g., TROP2)—to synergistically dismantle the tumor’s intrinsic survival fortress and extrinsic physical-immune barriers. Realizing this vision requires establishing a closed- loop, adaptive clinical framework. This entails replacing static protocols with dynamic adjustments guided by Qiao et al. Molecular Biomedicine (2026) 7:98 Page 21 of 28 real-time molecular surveillance and adopting multidi- mensional endpoints that assess ecosystem remodeling (stromal reorganization, immune infiltration) alongside tumor regression. Although formidable challenges per- sist in navigating tumor heterogeneity, a systems-biol- ogy approach integrating mechanistic dissection with interdisciplinary innovation offers the most rational path to transform cancer from a lethal disease into a manageable chronic condition.

  generalstated in future workevidence 5/5
  Keywords: tumor resistance dynamic cell mediated immune adaptive framework cancer static multidimensional ecosystem integrating intrinsic epigenetic
• Editorial: Progress in molecular mechanisms and targeted therapies for solid tumor microenvironments (2026) · Frontiers in Cell and Developmental Biology · doi

  Mechanistic studies should connect tumor-intrinsic signaling to immune, stromal, metabolic, and stress-response programs. - Biomarker development should progress from single-gene markers to multidimensional signatures. - Emerging approaches to TME remodeling and precision treatment should be further developed.

  generalstated in cells future researchevidence 5/5
  Keywords: mechanistic studies connect tumor-intrinsic signaling immune stromal metabolic

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