The tumor microenvironment (TME) plays a crucial role in shaping immune responses against tumors. Schürch et al. utilized a novel co-detection by indexing (CODEX) technique to analyze the spatial organization of immune cells at the invasive front of colorectal cancer (CRC). Their findings revealed that coordinated cellular neighborhoods are essential for effective antitumoral immunity, highlighting the importance of spatial interactions among immune cells and tumor cells (ref: Schürch doi.org/10.1016/j.cell.2020.07.005/). In a complementary study, Katzenelenbogen et al. introduced an integrated technology called INs-seq, which combines single-cell RNA sequencing with intracellular protein activity profiling. This approach uncovered an immunosuppressive role of TREM2 in cancer, suggesting that specific immune signaling pathways can be targeted to enhance antitumor responses (ref: Katzenelenbogen doi.org/10.1016/j.cell.2020.06.032/). Sadik et al. further explored the metabolic immune checkpoint IL4I1, which activates the aryl hydrocarbon receptor (AHR) and promotes tumor progression, indicating that metabolic pathways are critical in modulating immune responses in the TME (ref: Sadik doi.org/10.1016/j.cell.2020.07.038/). The complexity of the TME is also emphasized in a review of various models for immuno-oncology research, which discusses the strengths and limitations of different experimental systems, from cell co-cultures to organoids (ref: Unknown doi.org/10.1016/j.ccell.2020.07.010/). Lastly, the ESMO consensus conference recommendations on melanoma management underscore the need for a multidisciplinary approach to address the challenges posed by the TME in metastatic and locoregional melanoma (ref: Keilholz doi.org/10.1016/j.annonc.2020.07.004/; Michielin doi.org/10.1016/j.annonc.2020.07.005/).

Immune checkpoint inhibitors have revolutionized cancer therapy, yet challenges remain in enhancing their efficacy. Li et al. designed a chimeric antigen receptor (CAR) that prevents ubiquitination, thereby improving CAR-T cell persistence and antitumor efficacy. Their findings suggest that maintaining CAR surface expression is crucial for sustained immune responses (ref: Li doi.org/10.1016/j.immuni.2020.07.011/). Chapman et al. corroborated these findings by demonstrating that preventing CAR ubiquitination enhances T cell cytotoxicity and longevity, indicating that CAR recycling mechanisms can be exploited to improve therapeutic outcomes (ref: Chapman doi.org/10.1016/j.immuni.2020.07.023/). Morrissey et al. investigated the role of CD47 in immune evasion, revealing that its ligation can reposition the inhibitory receptor SIRPA to suppress phagocytosis, thus providing insights into mechanisms of immune resistance (ref: Morrissey doi.org/10.1016/j.immuni.2020.07.008/). Additionally, Liu et al. identified a pH-dependent binding hotspot on PD-L1 for monoclonal antibodies, which could enhance tumor therapy by improving antibody efficacy (ref: Liu doi.org/10.1038/s41392-020-00254-z/). Luo et al. demonstrated that mitomycin C enhances PD-L1 blockade efficacy in non-small cell lung cancer, suggesting that combining chemotherapy with immunotherapy may yield better clinical outcomes (ref: Luo doi.org/10.1038/s41392-020-0200-4/). Lastly, the development of engineered protein logic systems for precise cell targeting represents a novel approach to enhance the specificity and effectiveness of immunotherapies (ref: Lajoie doi.org/10.1126/science.aba6527/).

Innovative strategies in cancer immunotherapy are critical for improving patient outcomes. Kang et al. introduced T-cell-mimicking nanoparticles (TCMNPs) that can target tumors and induce apoptosis in cancer cells while being resistant to immunosuppressive factors, showcasing a promising alternative to traditional T cell therapies (ref: Kang doi.org/10.1002/adma.202003368/). Huang et al. focused on overcoming adaptive immune resistance in pancreatic cancer by inhibiting CDK1/2/5, which could enhance the efficacy of immunotherapies by reducing immune checkpoint expression (ref: Huang doi.org/10.1136/gutjnl-2019-320441/). Salzer et al. presented an AvidCAR platform that allows for combinatorial antigen recognition and reversible control of CAR function, addressing the challenges of specificity in solid tumors (ref: Salzer doi.org/10.1038/s41467-020-17970-3/). Hewitt et al. explored intratumoral IL12 mRNA therapy, which promotes a TH1 transformation of the TME, potentially enhancing local immune responses while minimizing systemic toxicity (ref: Hewitt doi.org/10.1158/1078-0432.CCR-20-0472/). Klein et al. reported that pleomorphic dermal sarcomas exhibit a high mutational load and an inflamed TME, indicating their susceptibility to immunotherapy (ref: Klein doi.org/10.1158/1078-0432.CCR-20-1899/). Axelrod et al. highlighted the impact of neoadjuvant chemotherapy on the immune microenvironment in breast cancer, revealing that changes in immune-related gene expression correlate with clinical outcomes (ref: Axelrod doi.org/10.1158/1078-0432.CCR-19-3685/). Lastly, Li et al. demonstrated that the burst release of annexin A5 from nanoparticles can enhance T cell responses by blocking apoptotic cell phagocytosis, providing a novel mechanism to boost anti-tumor immunity (ref: Li doi.org/10.1038/s41551-020-0599-5/).

Clinical outcomes in cancer immunotherapy are influenced by various factors, including patient demographics and tumor characteristics. Pinato et al. conducted a multi-center study on cancer patients with confirmed COVID-19, revealing that male gender, older age, and the presence of comorbidities significantly correlate with higher mortality rates, emphasizing the need for tailored management strategies in this vulnerable population (ref: Pinato doi.org/10.1158/2159-8290.CD-20-0773/). Maucourant et al. investigated natural killer (NK) cell immunotypes in COVID-19 patients, finding strong NK cell activation associated with disease severity, which could inform therapeutic approaches targeting innate immunity (ref: Maucourant doi.org/10.1126/sciimmunol.abd6832/). Hakimi et al. performed a pan-cancer analysis of PBAF complex mutations, concluding that these mutations do not correlate with improved overall survival in patients treated with immune checkpoint blockade, challenging previous assumptions about their role as biomarkers (ref: Hakimi doi.org/10.1038/s41467-020-17965-0/). The findings from these studies underscore the complexity of predicting immunotherapy responses and highlight the importance of identifying reliable biomarkers for patient stratification.

Vaccine development and antigen targeting are pivotal in advancing cancer immunotherapy. Pandey et al. identified mutated ELF3 as a potential vaccine candidate for gallbladder cancer through integrated genomic analysis, which could lead to targeted therapeutic strategies for this aggressive malignancy (ref: Pandey doi.org/10.1038/s41467-020-17880-4/). Fahed et al. examined the interplay between monogenic and polygenic risk factors in disease penetrance, providing insights that could inform personalized vaccine strategies based on individual genetic backgrounds (ref: Fahed doi.org/10.1038/s41467-020-17374-3/). Additionally, Klein et al. reiterated the susceptibility of pleomorphic dermal sarcomas to immunotherapy, suggesting that their high mutational burden could be leveraged for vaccine development (ref: Klein doi.org/10.1158/1078-0432.CCR-20-1899/). Hewitt et al. also highlighted the potential of intratumoral IL12 mRNA therapy to enhance local immune responses, which could complement vaccine strategies aimed at inducing robust antitumor immunity (ref: Hewitt doi.org/10.1158/1078-0432.CCR-20-0472/). These studies collectively emphasize the need for innovative approaches in vaccine development and antigen targeting to improve clinical outcomes in cancer patients.

Different cancer types require tailored therapeutic approaches to optimize treatment efficacy. Klein et al. provided a comprehensive analysis of pleomorphic dermal sarcomas, revealing their high mutational load and immunogenic TME, which suggests a strong susceptibility to immunotherapy (ref: Klein doi.org/10.1158/1078-0432.CCR-20-1899/). Hewitt et al. explored intratumoral IL12 mRNA therapy, demonstrating its potential to promote TH1 transformation in the TME, which could enhance responses in various cancers (ref: Hewitt doi.org/10.1158/1078-0432.CCR-20-0472/). The findings from these studies highlight the importance of understanding the unique characteristics of different cancer types to develop effective immunotherapeutic strategies. Additionally, the integration of novel therapeutic modalities, such as mRNA therapies, into existing treatment paradigms could significantly improve patient outcomes across diverse malignancies.

The management of adverse effects in immunotherapy is critical for improving patient outcomes. Tan et al. reported on a dominant-negative NFKBIA mutation that leads to severe immunodeficiency and autoinflammation, underscoring the need for careful monitoring of immune responses in patients undergoing immunotherapy (ref: Tan doi.org/10.1172/JCI98882/). Smith et al. evaluated the safety of autologous CMV-specific T cell therapy in glioblastoma multiforme, finding it to be a safe adjuvant treatment option, which could pave the way for further exploration of adoptive cellular therapies in this challenging cancer type (ref: Smith doi.org/10.1172/JCI138649/). Wudhikarn et al. analyzed infection rates in patients treated with CD19 CAR T cells, revealing that systemic corticosteroid use for managing cytokine release syndrome (CRS) or immune effector cell-associated neurotoxicity syndrome (ICANS) increases infection risk, highlighting the importance of balancing immunotherapy efficacy with the management of adverse effects (ref: Wudhikarn doi.org/10.1038/s41408-020-00346-7/). These studies collectively emphasize the need for ongoing vigilance and innovative strategies to manage adverse effects associated with immunotherapy, ensuring that patients can safely benefit from these transformative treatments.