These advances, major challenges remain

The gap

Evidence profile

Sourced from the future work of the source papers, classified as general, drawn from work published between 2025 and 2026, spanning 4 journals. Those papers have been cited 8 times in total.

Supporting evidence — 4 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 [1] Alsaafeen B H, Ali B R, Elkord E. Resistance mechanisms to immune checkpoint inhibitors: updated insights. Molecular cancer, 2025, 24(1): 20. [2] Wang J, Yan R, Jia D, et al. Reprogramming T cell stemness against cancer. Trends in cancer, 2026, 12(1): 68-79. [3] 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. [4] 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. [5] Tsui C, Kretschmer L, Rapelius S, et al. MYB orchestrates T cell exhaustion and response to checkpoint inhibition. Nature, 2022, 609(7926): 354-360. [6] 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. [7] Humblin E, Korpas I, Lu J, et al. Sustained CD28 costimulation is required for self-renewal

  generalfuture work
  Keywords: tpex immunotherapy differentiation cancer exhaustion self renewal tumor immune checkpoint cells wang cell hierarchy potential
• Immunotherapy Landscape of Advanced Clear Cell Renal Cell Carcinoma: Targeting the Cancer-Immunity Cycle and Future Perspectives (2026) · Biomedicines · doi

  While IO+TKI combinations have redefined first-line care for advanced RCC, primary resistance occurs in about 20–30% of patients, and acquired resistance eventually develops in most patients. It suggests to us that existing therapies, while a good starting point, are far from an end point. Future explorations in immunotherapy, particularly multi-immune checkpoint combinations, IO + metabolic modulation, and personalized immunotherapy, show great promise. PD-1+CTLA-4 dual immunotherapy (nivolumab + ipilimumab) has achieved good results in renal cancer, and has become one of the first-line options for intermediate and high-risk patients. This validates the feasibility of targeting multiple immune checkpoints simultaneously. On this basis, other ICI combination regimens with complementary mech- anisms, such as PD-1+LAG-3 and PD-1+TIGIT, are becoming hot future research directions. The core reason is that the compensatory upregulation of inhibitory receptors such as LAG- 3 and TIGIT after PD-1 blockade is the core mechanism of acquired drug resistance, which cannot be solved by simply increasing the dose of PD-1 or replacing antibodies, and these compensatory pathways must be targeted at the same time. From the perspective of clinical positioning, the core value of this new combination strategy is mainly that for patients with disease progression after PD-1 treatment and tumors expressing LAG-3 or TIGIT, the combination of corresponding inhibitors is the most direct rescue plan. The feasibility and safety of using these novel combinations to prevent drug resistance at the time of initial treatment also warrant further exploration. Despite limited progress in exploring new immune checkpoints in recent years, future research should focus on how best to utilize existing targets. One approach would be multi-target network blockade, simultaneously targeting PD-1, LAG-3, TIGIT and other molecules to break the compensatory network. Another approach could involve sequential blockade, using corresponding inhibitors based on the upregulation of different checkpoints during resistance evolution. Regardless of the approach, the key lies in personalized treatment, namely selecting the appropriate combination based on profiling receptor expression in patient tumor tissues. The potential of IO + metabolic modulation arises from a deeper understanding of RCC’s metabolic characteristics. While IO+TKI effectively inhibits the VEGF pathway, the metabolic dysregulation in RCC’s tumor microenvironment is multifaceted. Lactate accumulation, IDO-mediated tryptophan depletion, and hypoxia-induced activation of the adenosine pathway all form a deeper immune-suppressive network that TKI cannot fully resolve. In this context, HIF-2α inhibitors like belzutifan have emerged. HIF-2α is a key molecule in the core RCC driver pathway (VHL-HIF-VEGF axis). Belzutifan inhibits HIF-2α, blocking both VEGF expression and hypoxia-induced metabolic reprogramming upstream, and has synergis

  generalfuture work
  Keywords: resistance metabolic patients immune combination tigit core combinations future immunotherapy checkpoints compensatory blockade treatment inhibitors
• 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.

  generalfuture work
  Keywords: tumor resistance dynamic cell mediated immune adaptive framework cancer static multidimensional ecosystem integrating intrinsic epigenetic
• T-cell exhaustion in COVID-19: what do we know? (2025) · Frontiers in Immunology · cited 8× · doi

  Despite these advances, major challenges remain. Methodological gaps persist, including limited longitudinal studies, incomplete profiling of T-cell subsets, and the absence of validated clinical biomarkers. Therapeutic strategies such as those involving checkpoint inhibitors, metabolic enhancers, cytokine modulators, and epigenetic agents are promising but remain experimental and must balance immunity reinvigoration with inflammation control. Looking forward, three priorities are clear: (1) systematically incorporating exhaustion markers into clinical immunophenotyping, particularly in severe and Long COVID; (2) tailoring therapies through patient stratification to identify those most likely to benefit from reinvigoration strategies; and (3) designing next-generation vaccines that optimize not only antibody durability but also exhaustion-resistant T-cell responses. Beyond COVID-19, the rapid onset and persistence of exhaustion observed here challenge paradigms from chronic infection and cancer models, urging a redefinition of how this dysfunctional state is understood and targeted across infectious and non- infectious diseases.

  generalfuture work
  Keywords: exhaustion remain cell clinical strategies reinvigoration covid infectious despite advances major challenges methodological gaps persist

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