The tumor microenvironment (TME) plays a critical role in shaping immune responses, particularly through the differentiation of monocytes into tumor-associated macrophages (TAMs) rather than dendritic cells (DCs). Devalaraja et al. demonstrated that tumor-derived retinoic acid (RA) promotes this differentiation, leading to an immunosuppressive environment that hinders effective immune responses (ref: Devalaraja doi.org/10.1016/j.cell.2020.02.042/). In the context of lung cancer, the PACIFIC trial highlighted the efficacy of durvalumab, an anti-PD-L1 antibody, showing significant improvements in progression-free survival (PFS) and overall survival (OS) across various PD-L1 expression levels (ref: Paz-Ares doi.org/10.1016/j.annonc.2020.03.287/). This underscores the importance of PD-L1 as a biomarker for immunotherapy response, as further explored by Schoenfeld et al., who identified specific molecular correlates of PD-L1 expression in lung adenocarcinomas (ref: Schoenfeld doi.org/10.1016/j.annonc.2020.01.065/). Moreover, the role of dendritic cells in mediating responses to PD-L1 blockade was emphasized by Mayoux et al., who found that these cells are crucial for instigating anticancer immunity, suggesting that enhancing DC function could improve therapeutic outcomes (ref: Mayoux doi.org/10.1126/scitranslmed.aav7431/). Contradictory findings emerged in pancreatic cancer, where Hegde et al. reported that neoantigen expression exacerbates a fibro-inflammatory microenvironment, leading to immune evasion and disease progression (ref: Hegde doi.org/10.1016/j.ccell.2020.02.008/). This highlights the complexity of the TME and the need for tailored immunotherapeutic strategies based on tumor type and microenvironmental context.

Research into tumor immunogenicity has revealed critical insights into how tumors evade immune surveillance. Liu et al. demonstrated that ADORA1 inhibition promotes immune evasion by regulating the ATF3-PD-L1 axis, enhancing the efficacy of PD-1 blockade in melanoma and non-small cell lung cancer (NSCLC) models (ref: Liu doi.org/10.1016/j.ccell.2020.02.006/). This finding aligns with the broader theme of immune evasion mechanisms, particularly in pancreatic cancer, where Hegde et al. found that a lack of dendritic cells leads to dysfunctional immune surveillance, allowing tumors to progress unchecked (ref: Hegde doi.org/10.1016/j.ccell.2020.02.008/). Bednar et al. further explored the context-dependent immune responses in pancreatic cancer, highlighting the challenges of extending immunotherapy benefits to this malignancy due to its unique immune landscape (ref: Bednar doi.org/10.1016/j.ccell.2020.02.010/). The study by Algazi et al. on the intratumoral delivery of IL-12 showed promising systemic immune responses in metastatic melanoma, suggesting that enhancing local immune activation could counteract immune evasion (ref: Algazi doi.org/10.1016/j.annonc.2019.12.008/). These findings collectively emphasize the need for innovative strategies to overcome immune evasion, such as combination therapies that target multiple pathways involved in tumor immunity.

The exploration of novel immunotherapy strategies has gained momentum, particularly in enhancing the efficacy of existing treatments. Crinier et al. provided a comprehensive overview of natural killer (NK) cells, highlighting their potential as therapeutic targets in solid tumors and hematological malignancies due to their innate cytotoxic capabilities (ref: Crinier doi.org/10.1016/j.cell.2020.02.029/). Liu et al. further contributed to this theme by demonstrating that ADORA1 inhibition can enhance the effectiveness of PD-1 blockade in melanoma and NSCLC, suggesting a synergistic approach to immunotherapy (ref: Liu doi.org/10.1016/j.ccell.2020.02.006/). Additionally, the combination of PD-1 inhibitors with OX40 agonists showed promising results in mouse models of pancreatic cancer, leading to tumor rejection and the establishment of immune memory (ref: Ma doi.org/10.1053/j.gastro.2020.03.018/). This study underscores the potential of combination therapies to enhance immune responses against tumors that typically exhibit resistance to single-agent therapies. The findings from Necchi et al. on the impact of molecular subtyping and immune infiltration on responses to neoadjuvant pembrolizumab in muscle-invasive bladder cancer further illustrate the importance of personalized approaches in immunotherapy (ref: Necchi doi.org/10.1016/j.eururo.2020.02.028/). Collectively, these studies highlight the evolving landscape of immunotherapy, emphasizing the need for innovative combinations and strategies to improve patient outcomes.

The integration of cancer genomics and biomarker discovery into immunotherapy has become increasingly important for predicting treatment responses. Schoenfeld et al. conducted a comprehensive analysis of PD-L1 expression in lung adenocarcinomas, revealing that specific molecular features are associated with differential PD-L1 expression, which may influence the predictive capacity of PD-L1 for immune checkpoint inhibitors (ref: Schoenfeld doi.org/10.1016/j.annonc.2020.01.065/). This study underscores the necessity of understanding the genomic landscape of tumors to tailor immunotherapeutic strategies effectively. In the context of pancreatic cancer, Hegde et al. highlighted how neoantigen expression can lead to immune evasion, emphasizing the need for genomic insights to develop effective immunotherapies (ref: Hegde doi.org/10.1016/j.ccell.2020.02.008/). Furthermore, the study by Algazi et al. on the intratumoral delivery of IL-12 demonstrated significant systemic immune responses, suggesting that genomic profiling could help identify patients most likely to benefit from such interventions (ref: Algazi doi.org/10.1016/j.annonc.2019.12.008/). These findings collectively illustrate the critical role of cancer genomics in informing immunotherapy approaches and the potential for biomarkers to guide treatment decisions.

Clinical trials have been pivotal in establishing the efficacy of immunotherapy across various cancer types. The PACIFIC trial, as reported by Paz-Ares et al., demonstrated that durvalumab significantly improved progression-free and overall survival in patients with unresectable stage III NSCLC, highlighting the importance of PD-L1 expression in predicting treatment outcomes (ref: Paz-Ares doi.org/10.1016/j.annonc.2020.03.287/). This trial's results underscore the necessity of stratifying patients based on PD-L1 expression levels to optimize therapeutic benefits. Schoenfeld et al. further reinforced this notion by correlating clinical outcomes with molecular features in lung adenocarcinoma, suggesting that tailored approaches based on genomic profiling could enhance the predictive accuracy of immunotherapy responses (ref: Schoenfeld doi.org/10.1016/j.annonc.2020.01.065/). Additionally, Algazi et al. reported promising results from the intratumoral delivery of IL-12, with a notable objective response rate in metastatic melanoma patients, indicating that localized immune activation could be a viable strategy in clinical settings (ref: Algazi doi.org/10.1016/j.annonc.2019.12.008/). Collectively, these studies highlight the evolving landscape of clinical trials in cancer immunotherapy, emphasizing the need for continuous evaluation of treatment strategies to improve patient outcomes.

Adjuvant and neoadjuvant immunotherapy approaches are gaining traction as strategies to enhance treatment efficacy in various cancers. Algazi et al. reported on the intratumoral delivery of tavokinogene telseplasmid, which yielded systemic immune responses in metastatic melanoma patients, demonstrating a 35.7% overall response rate in the main study (ref: Algazi doi.org/10.1016/j.annonc.2019.12.008/). This highlights the potential of localized immunotherapy to stimulate broader systemic effects, particularly in the adjuvant setting. Moreover, the combination of PD-1 inhibitors with OX40 agonists showed promising results in mouse models of pancreatic cancer, leading to tumor rejection and the establishment of immune memory, suggesting that such combinations could be effective in neoadjuvant settings (ref: Ma doi.org/10.1053/j.gastro.2020.03.018/). The study by Necchi et al. on the impact of molecular subtyping and immune infiltration on responses to neoadjuvant pembrolizumab in muscle-invasive bladder cancer further emphasizes the importance of tailoring immunotherapy approaches based on individual patient characteristics (ref: Necchi doi.org/10.1016/j.eururo.2020.02.028/). Collectively, these findings underscore the necessity of integrating innovative immunotherapeutic strategies into adjuvant and neoadjuvant treatment paradigms to enhance patient outcomes.