The processes underlying ICI resistance are not fully understood, some mechanisms influencing primary resistance

The gap

Evidence profile

Sourced from the future work and discussion of the source papers, classified as general, drawn from work published between 2024 and 2026, spanning 7 journals. Those papers have been cited 191 times in total.

Supporting evidence — 8 representative gaps

• Breast cancer chemotherapy in transition: predictive markers, resistance mechanisms, and new treatment approaches (2026) · Frontiers in Oncology · doi

  The advancement of chemotherapy in breast cancer is moving toward personalization rather than abandonment. Chemotherapy will likely remain essential for many patients, but its delivery is becoming more selective, adaptive, and biologically integrated. Future progress will depend on refining predictive markers, espe- cially through multimodal approaches that combine genomic alter- ations, immune contexture, molecular subtyping, and dynamic biomarkers such as ctDNA. Better identification of true chemosensitive disease could minimize toxicity in low-benefit populations while enabling rational escalation in high-risk groups. At the same time, overcoming resistance will require moving beyond single-marker thinking. Resistance is rarely explained by one pathway alone; instead, it reflects evolving tumor ecosystems. Integrative profiling before, during, and after treatment may allow clinicians to identify emerging resistant clones and modify therapy accordingly. The neoadjuvant setting remains ideal for this research because it offers serial tissue access and direct assessment of response. Finally, future therapeutic strategies will likely blend chemo- targeted agents, and post- therapy with immunotherapy, neoadjuvant residual disease–directed interventions. Emerging platforms such as antibody-drug conjugates further suggest that

  generalfuture work
  Keywords: chemotherapy moving likely future disease resistance emerging therapy neoadjuvant advancement breast cancer toward personalization rather
• Emerging Therapeutic Strategies in Metastatic Hormone-Sensitive Prostate Cancer (2026) · Journal of Immunotherapy and Precision Oncology · doi

  Advancements in immunology and the mechanisms of tumor immune evasion have positioned immuno- therapy as a revolutionary treatment approach across oncology, as seen in melanoma, renal cell carcinoma, breast cancer, and lung cancer.[54] These outcomes sparked interest in immunotherapy for metastatic prostate cancer. In this review, we will focus on immune checkpoint inhibitors (ICIs). Programmed death (PD) inhibitors, such as nivolumab and pembro- lizumab, enable immune targeting of tumor cells. Following an immune response, the immune system downregulates itself via cytotoxic T-lymphocyte–asso- ciated protein 4 (CTLA-4). CTLA4 inhibitors like ipili- mumab perpetuate the immune response to target tumor cells.[55] In 2011, the FDA first approved ipili- mumab for advanced melanoma, as it demonstrated improved OS.[56] Immunotherapy in metastatic castration- resistant prostate cancer (mCRPC) Despite the success in other tumor types, trials assess- ing the efficacy of immunotherapy in prostate cancer have not been compelling. In 2014, Kwon et al[57] found no difference in OS in patients with mCRPC who pro- gressed after chemotherapy and received ipilimumab, although they noted a slight benefit in PFS. These results were largely replicated in 2016 in chemotherapy-naive mCRPC, although with slightly improved PFS and PSA response rates.[58] For pembrolizumab, the phase 1b KEYNOTE-028 trial showed initial promise against mCRPC.[59] Of the 23 patients who received pembrolizumab, 4 had partial responses (objective response rate [ORR] 17.4%, 95% CI, 5.0%–38.8%). Pembrolizumab resulted in a mean duration of response of 13.5 months and increased median PFS and OS in heavily pretreated programmed death ligand 1 (PD-L1)-positive mCRPC. The subse- quent phase II KEYNOTE-199 trial evaluated pembroli- zumab in mCRPC with prior docetaxel and one or h t t p : / / c r e a t i v e c o m m o n s . o r g / l i c e n s e s / b y - n c - n d / 4 . 0 / l D o w n o a d e d f r o m h t t p s : / / i n n o v a t i o n s o u r n a s - j i l j l p o . k g m e r i d a n . c o m a t i 2 0 2 6 - 0 7 - 0 6 i v a O p e n A c c e s s . i T h s w o r k i s p u b l i s h e d u n d e r - - a C C B Y N C N D 4 - . 0 I n t e r n a t i o n a l i L c e n s e .

  generalfuture work
  Keywords: immune mcrpc cancer response tumor immunotherapy prostate inhibitors pembrolizumab melanoma metastatic programmed death cells ctla
• Advances in Radiotherapy for Soft Tissue Sarcomas in 2025: A Review (2026) · Current Oncology Reports · doi

  ● Integration of Biomarkers for Personalized RT: The future lies in moving beyond a one-size-fits-all ap- proach. The integration of histotype-specific response patterns [2], molecular profiles (e.g., CINSARC [42], PARP expression [25]), and real-time response data from mpMRI [23] or circulating tumor DNA will enable truly personalized RT prescriptions. Future trials must stratify patients using these biomarkers to test adaptive dose escalation, de-escalation, or specific combinatorial strategies. ● Next-Generation Systemic-RT Combinations and Sequencing: Building on early successes with PARPi and ICIs, research must optimize the sequencing, tim- ing, and dosing of these combinations. Furthermore, exploring novel agents (e.g., next-generation anti-an- giogenics, bispecific antibodies) and cellular therapies (CAR-T/NK cells) in combination with RT, guided by predictive biomarkers of synergy, represents a fertile frontier [12, 29]. ● AI-Enhanced Adaptive Radiotherapy and Quanti- tative Response Assessment: The fusion of artificial intelligence (AI) with adaptive RT platforms will be transformative. AI algorithms can automate the analy- sis of mpMRI and other imaging data to predict early response, enabling fully dynamic treatment adaptation [22]. Similarly, AI can aid in validating and standardiz- ing novel surrogate endpoints like hyalinization [28] or radiomic signatures, accelerating trial conduct. ● Validation of Surrogate Markers: Surrogate markers such as hyalinization [28], monocyte infiltration [41], and mpMRI parameters [23] need validation in large- scale prospective, multi-institutional trials to potentially replace traditional endpoints (e.g., OS, PFS) in clinical trials. This would accelerate the development of novel RT strategies by reducing trial duration and sample size requirements. ● Standardized QoL Measurement and Value-Based Care: Implementation of standardized QoL tools such as STS-QoL [43] in clinical practice and trials will enable Page 11 of 15 50 consistent monitoring of patient-reported outcomes. Fu- ture research should focus on identifying interventions to mitigate QoL declines during RT (e.g., supportive care, rehabilitation) and correlating QoL with long- term functional outcomes. Integrating patient-reported outcomes into clinical decision-making is essential for value-based oncology care. ● Global Access to Advanced RT Technologies: Ad- dressing disparities in access to hypofractionation, par- ticle therapy, and adaptive RT is critical. Foppele et al. [5] showed that hypofractionation can be implemented in resource-limited settings during the pandemic, and future efforts should focus on expanding access to cost- effective advanced RT technologies worldwide. This includes technology transfer, training, and the develop- ment of simplified yet effective hypofractionated proto- cols suitable for diverse healthcare environments.

  generalfuture work
  Keywords: response trials adaptive biomarkers future mpmri novel surrogate clinical care outcomes access integration personalized size
• Mechanisms of immune checkpoint inhibitors: insights into the regulation of circular RNAS involved in cancer hallmarks (2024) · Cell Death and Disease · cited 159× · doi

  Over the past decade, ICIs have been developed and approved for clinical use in multiple cancer types at an unprecedented rate. Despite tremendous progress, ICIs have not completely solved the problem of cancer treatment. Besides discovering biomarkers to predict the efficacy and safety of ICIs, more immune checkpoint molecules may need to be identified in the next decade to provide more options for immunotherapy and bring treatment opportunities to more patients, which depends on our insights into the mechanisms of immune checkpoint regulation. This review sum- marizes the status quo of frequent immune checkpoints and ICIs commonly applied in cancer, such as anti-PD-1/PD-L1, anti-CTLA-4, anti-LAG-3, anti-TIM-3, and other immune checkpoints targeted mAbs. The regulatory mechanisms of immune checkpoints are complex and unclear, which stem from its complicated and diverse influencing factors, involving ncRNAs, proteins, and other elements. As a class of abundant component of the human transcriptome involved in cancer hallmarks, ncRNAs are closely associated with the expression regulation of the structure’s stability, circRNAs present significantly greater advantages and potential as diagnostic and prognostic biomarkers for cancer management than other types of ncRNAs. Also, circRNAs have been confirmed to involve in various cancer hallmarks including prolifera- tion, cell death, inflammation, angiogenesis, invasion and metastasis interacting with proteins, through functioning as miRNA sponge, encoding proteins, or other unclarified mechanisms. immune checkpoints.

  generalfuture work
  Keywords: cancer immune icis checkpoints anti mechanisms ncrnas proteins decade types treatment biomarkers checkpoint regulation hallmarks
• Immunotherapy and Hepatocellular Carcinoma: From Tumor-Immune Cell Interactions to Rational Therapeutic Strategies (2026) · Cells · doi

  6.1. Overview Immunotherapy has transformed the treatment landscape of HCC, yet clinical benefit is determined less by the nominal regimen selected than by the immune architecture of the individual tumor. In this review, we used the cancer immunity cycle not as a generic conceptual frame but as an HCC-specific map of where anti-tumor immunity fails: at the level of priming, trafficking, effector rescue, stromal exclusion, metabolic suppression, and etiology-conditioned immune dysfunction. From this perspective, the major contribution of modern combination therapy is not simply additive efficacy but active remodeling of the dominant biological barrier that limits checkpoint activity in a given tumor. This same framework also explains why rational combinations do not succeed uni- versally. Response fails when the selected regimen leaves the dominant barrier intact, whether that barrier is tumor-cell autonomous, microenvironmental, treatment-induced, or etiology-specific. Future progress will therefore likely require closer alignment between therapies that target specific resistance mechanisms and biomarkers that identify which resistance layer is most relevant in each patient. Table 2 summarizes this framework by linking dominant barriers to representative biology or biomarkers, therapeutic rationale, example strategies, and current clinical applicability. Table 2. Barrier-based framework for HCC immunotherapy. This table is intended as a conceptual organizing aid; dominant barriers are rarely measured prospectively, and the listed biomarkers are not validated for treatment selection unless explicitly stated. Representative evidence is discussed and cited in the corresponding sections of the text.

  generalfuture work
  Keywords: tumor dominant barrier treatment specific framework biomarkers immunotherapy clinical regimen selected immune immunity conceptual fails
• Patient-derived three-dimensional lung tumor models to evaluate response to therapy (2026) · npj Precision Oncology · doi

  While the processes underlying ICI resistance are not fully understood, some mechanisms influencing primary resistance, including tumor intrinsic factors (lack of tumor immunogenicity, loss of tumor antigen or HLA expression and aberrant signaling) and extrinsic factors (presence of immune suppressive cell populations, T cell exhaustion and upregulation of alternative immune checkpoints, and altered metabolism) have been described41,47-52 53-55. Distinct from prior reports, Several prior studies have identified key human TME components, such as tumor-infiltrating biomarkers of resistance and clinical outcome are lacking55.

  generaldiscussion
  Keywords: tumor resistance factors immune cell prior processes underlying fully understood mechanisms influencing primary including intrinsic
• Impact of metastatic pattern and histologic subtype on PD-(L)1 inhibitor efficacy in HER2-negative advanced gastric and gastroesophageal cancer: a meta-analysis (2026) · Frontiers in Oncology · doi

  Future research should focus on integrating spatial and single- cell immune profiling to elucidate mechanisms of resistance to immune checkpoint inhibition in peritoneal and diffuse-type dis- ease. Evaluating mechanism-driven combination regimens, includ- ing PD-(L)1 inhibitors paired with anti-fibrotic, anti-VEGF, or anti- TGF-b agents, as well as locoregional therapies like HIPEC or PIPAC may help remodel immune-TME and enhance therapeutic response. Several of these strategies are currently under investiga- tion in preclinical models or early-phase trials in GC, including intraperitoneal chemotherapy combined with immune checkpoint inhibitor (22–24, 27). In parallel, prospective, biomarker-driven clinical trials stratified by histologic subtype and metastatic pattern are warranted to validate subgroup-specific therapeutic strategies. Finally, the incorporation of immune gene expression signatures could enable real-time monitoring of treatment response and resistance evolution.

  generalfuture work
  Keywords: immune anti resistance checkpoint driven therapeutic response strategies trials future focus integrating spatial single cell
• Revisiting immune checkpoint inhibitors: new strategies to enhance efficacy and reduce toxicity (2024) · Frontiers in Immunology · cited 32× · doi

  6 Conclusion The future of immune checkpoint inhibitor (ICI) therapy lies in overcoming current limitations and expanding the therapeutic potential of these powerful treatments. One of the most promising avenues is the development of next-generation ICIs that offer enhanced selectivity and reduced toxicity (55). Advances in biotechnology are paving the way for engineered antibodies, bispecific molecules, and novel immune checkpoint targets that could provide more effective and safer cancer treatments. These innovations have the potential to broaden the applicability of ICIs to a wider range of cancers, including those that are currently resistant to existing therapies. Importantly, the development of more effective and targeted ICIs may have a positive impact on the cost - effectiveness of ICI therapy. For example, if next - generation ICIs with higher response rates can be developed, it may reduce the need for multiple lines of treatment or combination therapies that are often costlier. Additionally, improved biomarkers for patient selection could ensure that ICIs are prescribed to those who are most likely to benefit, thereby avoiding unnecessary treatment costs for non - responders. In addition to new drug development, ongoing research is focused on better understanding the mechanisms of resistance to ICIs (56). By identifying the genetic and molecular factors that contribute to primary and acquired resistance, researchers can develop combination strategies that target these pathways and restore sensitivity to ICIs. Furthermore, the integration of biomarkers into clinical practice will allow for more personalized treatment approaches, ensuring that patients receive therapies most likely to be effective based on their individual tumor characteristics. Another key direction involves refining the timing and sequencing of ICIs in combination with other treatment modalities, such as chemotherapy, radiotherapy, and targeted therapies. Optimizing these combinations can enhance therapeutic outcomes while minimizing adverse effects. As research continues to evolve, there is also growing interest in exploring ICIs in non-cancer indications, potentially opening new frontiers in the treatment of autoimmune diseases and chronic infections. Together, these efforts promise to shape the future of cancer therapy, making ICIs a cornerstone of precision oncology. 6.1 Summary of key points In summary, ICIs have revolutionized cancer therapy, offering significant benefits but also presenting challenges such as variability in patient response and the risk of irAEs. Advances in biomarker- guided therapy, combination strategies, and the engineering of next-generation ICIs hold promise for overcoming these limitations. Ongoing research into optimizing dosing, patient management, and resistance mechanisms is crucial for enhancing the efficacy and safety of ICIs. By refining these strategies, ICIs can be more effectively integrated into personalized cancer treatment, improving outcomes for a broader range of patients. 6.2 Call to action The continued success of ICIs in cancer therapy hinges on the collaborative efforts of researchers, clinicians, and industry leaders. To fully realize the potential of ICIs, it is essential to prioritize research into understanding and overcoming resistance mechanisms, developing more precise biomarkers, and engineering next-generation ICIs with improved safety profiles. Clinicians must adopt a multidisciplinary approach to patient management, ensuring early detection and prompt intervention for irAEs. Additionally, there is a need for ongoing education and training to help healthcare professionals stay informed about the latest advancements in ICI therapy. By fostering innovation, collaboration, and education, the oncology community can enhance the effectiveness of ICIs, making these therapies more accessible and beneficial to a wider range of patients. The time to act is now, as the ongoing refinement of ICI strategies will be crucial in shaping the future of cancer treatment. 6.3 Implications for future cancer therapy The advancements and refinements in immune checkpoint inhibitor (ICI) therapy are poised to significantly impact the future of cancer treatment. As we continue to develop more

  generalfuture work
  Keywords: icis therapy cancer treatment future therapies next generation combination patient ongoing resistance strategies immune checkpoint

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