Regulatory T (Treg) cells play critical roles in maintaining immune tolerance and tissue homeostasis, but impede anti-tumor immunity. Recent work has established how Treg cells metabolically adapt within the tumor microenvironment (TME), and these adaptations frequently provide a functional advantage over effector T cells. Further, enhanced Treg cell function in the TME may contribute to the limited efficacy of current immunotherapies, especially immune checkpoint blockade (ICB). Here, we review recent progress in understanding mechanisms of Treg cell heterogeneity and function in tumors, with a particular focus on cellular metabolism as an underlying factor by which Treg cells are uniquely poised to thrive in the TME and contribute to tumorigenesis. We describe how cellular metabolism and nutrient or metabolic communication shape Treg cell lineage identity and function in the TME. We also discuss the interplay between ICB and Treg cell metabolism and function, and highlight current strategies targeting Treg cell metabolism specifically in the TME. Understanding metabolic control of intratumoral Treg cells provides excellent opportunities to uncover new or combination therapies for cancer.

Pharmacological treatment of malignant tumors in obese patients has been reported from several perspectives. Physiological changes may affect the kinetics of anticancer drugs (e.g., lipophilicity, distribution volume, and metabolism), consequently affecting their efficacy and safety profile. However, specific guidelines for antineoplastic agent dose adjustment according to body weight, mainly due to the under-representation of obese patients in clinical trials, are currently lacking. Moreover, considering that certain tumor development is associated with obesity, the clinical management of obese patients is often complex. We herein report the antitumor treatment options of three obese patients with malignant tumors and review relevant literature to analyze the dosage of antitumor drugs in this setting. This study aims to provide additional data for the clinical treatment of obese patients with malignant tumors.

In Case 1, carboplatin was administered at a fixed dose, mainly because of neurotoxicity risk. A maximum creatinine clearance rate (glomerular filtration rate) of 125 mL/min is recommended to prevent carboplatin overdose and toxicity. The maximum carboplatin dose was calculated using the following formula: maximum dose = area under the curve (AUC) × (125 + 25). Methotrexate dose was calculated based on the actual body weight of Cases 2 and 3. While receiving methotrexate, the blood drug concentration was within the reference range (24-h reference concentration ≤ 10 μmol/L), and no serious adverse reactions occurred. As seen in the three cases, considering the particularity of some drugs, for example, more than 90% of carboplatin is excreted through the kidney, carboplatin should be administered at a fixed dose, while other chemotherapy drugs can be administered according to the actual body weight as much as possible according to the patient's condition.

The toxicity of chemotherapy has traditionally been assessed based on the actual body weight of obese and non-obese patients. In clinical practice, overweight and obese cancer patients often receive reduced doses of chemotherapy drugs. According to the guidelines set by the American Society of Clinical Oncology, the positive association between the use of chemotherapy and treatment-related toxicity in obese patients lacks evidence. After comprehensive consideration of complications, chemotherapy dose should be determined based on the body surface area(BSA) calculated based on actual body weight, rather than estimated or idealized body weight.

The relationship between breast cancer prognosis, Body Mass Index (BMI), and endocrine therapy outcomes remains inconclusive. This study examines BMI's impact on survival outcomes in breast cancer patients receiving endocrine therapy through Mendelian randomization (MR) and a comprehensive clinical data review.

A meta-analysis of clinical studies up to January 2024 investigated the association between obesity and the efficacy and safety of endocrine therapy. Additionally, a two-sample MR approach using genetic variants evaluated the causal effect of BMI on survival in breast cancer patients undergoing endocrine therapy.

Meta-analysis of eight studies (n = 12,673) found that BMI generally does not affect therapy outcomes. However, subgroup analysis showed that overweight patients on anastrozole had shorter disease-free survival (DFS) than normal-weight patients (Hazard Ratio (HR) = 1.21, P = 0.03), increased fatigue (Risk Ratio (RR) = 0.91, P = 0.03), and higher nausea with cyclin-dependent kinase 4/6(CDK4/6)inhibitors (Risk Ratio, RR = 0.69, P < 0.0001). Normal-weight patients on tamoxifen had a greater risk of bone pain (RR = 1.25, P = 0.03). Further MR analysis revealed no causal link between BMI and 5-year or 15-year survival rates in endocrine-treated patients (5-year HR = 0.7923, 95 % Confidence Interval (CI)[0.2053, 3.0581], P = 0.7355; 15-year HR = 0.9793, 95 % CI [0.7121, 1.3469], P = 0.898).

Current meta-analysis and MR findings suggest no significant link between BMI and the overall efficacy of endocrine therapy in breast cancer. However, BMI should be considered in anastrozole therapy due to differential effects on DFS and adverse events.

Obesity is a condition of excess body fat. Although it has been identified as a risk factor for multiple cancers in part because of its 'metainflammatory' state, it has also been paradoxically associated with improved response to immune checkpoint inhibition. To study obesity, one must first understand how best to define it. In this opinion article, we briefly discuss factors that are impacting net effects of obesity and highlight complementary measures that should be considered beyond body mass index (BMI) when attempting to assess the potential effects of obesity in cancer.

The number of older adults with cancer will significantly grow in the coming decades. 45 % of older adults with gynecologic cancer are estimated to be affected by frailty. Frailty is a state of reduced physiologic reserve and decreased resiliency resulting in increased vulnerability to stressors. Importantly, frailty can exist in conjunction, but is not synonymous, with chronological age and older adults can be a heterogenous population. Routine assessment of frailty can help providers prevent both over- and under-treatment. The purpose of this review to describe the current state of literature on frailty as it relates to gynecologic cancer and draw from other literature including geriatrics, medical oncology, and surgery to suggest approaches to care. Frail patients have increased rates of surgical morbidity and mortality, higher toxicity to systemic therapy, and lower overall survival. Principles of the 5Ms (mobility, multi-complexity, mind, medications, and matters most) can be used in the clinic to guide care for older vulnerable (at risk) or frail adults. Surgical and medical oncology literature consistently indicates improved outcomes when multi-disciplinary approaches are used with routine frailty assessment. Future work is urgently needed to add validated geriatric measurements and outcomes into therapeutic trials and evaluate the impact of treatment choices on outcomes important to older adults such as functional recovery.

Higher body mass index (BMI) is reportedly associated with improved prognosis of patients with various cancers. However, it is unclear whether this phenomenon, also known as the obesity paradox, applies to metastatic renal cell carcinoma (mRCC). We aimed to determine the prognostic significance of BMI in patients with mRCC receiving first-line therapies.

We retrospectively reviewed patients with mRCC receiving first-line immune checkpoint inhibitor (ICI)-based combination therapy or tyrosine kinase inhibitor monotherapy. Overall survival (OS) was defined as the time from systemic therapy initiation to death from any cause or last follow-up. Baseline patient characteristics were compared by Mann-Whitney U test or Fisher's exact test. OS curves were constructed by Kaplan-Meier estimates and were compared by log-rank test. Multivariable analysis was performed via Cox proportional-hazards regression.

Of the 183 patients included, 130 (71 %) were overweight (≥22 and 18 kg/m2 in men and women, respectively), and 63 (34 %) received ICI-based combination therapy. There was a significantly higher proportion of men in the overweight subgroup (87 % versus 64 %; P = 0.002). During the study period, 97 patients died, and median (95 % confidence interval) OS was 39.0 months (31.5-66.3 months) and 28.1 months (17.6-39.7 months) in overweight and normoweight patients, respectively (P = 0.015). On multivariable analysis, overweight was independently associated with longer OS (HR 0.57; P = 0.014). Subgroup analyses of patients receiving ICI-based combination therapy yielded similar results.

Overweight is associated with favorable outcomes in patients with mRCC receiving first-line therapies.

GPER is broadly expressed in human tissues and has tumor-suppressive activity. No FDA-approved agents selectively target GPER. LNS8801 is a synthetic, orally bioavailable, enantiomerically pure, GPER agonist with potent anticancer activity in vivo. LNS8801 response is attenuated by a common germline coding variant present in roughly half of humans.

Metabolic reprogramming of cancer cells and the tumour microenvironment are pivotal characteristics of cancers, and studying these processes offer insights and avenues for cancer diagnostics and therapeutics. Recent advancements have underscored the impact of host systemic features, termed macroenvironment, on facilitating cancer progression. During tumorigenesis, these inherent features of the host, such as germline genetics, immune profile and the metabolic status, influence how the body responds to cancer. In parallel, as cancer grows, it induces systemic effects beyond the primary tumour site and affects the macroenvironment, for example, through inflammation, the metabolic end-stage syndrome of cachexia, and metabolic dysregulation. Therefore, understanding the intricate metabolic interplay between the tumour and the host is a growing frontier in advancing cancer diagnosis and therapy. In this Review, we explore the specific contribution of the metabolic fitness of the host to cancer initiation, progression and response to therapy. We then delineate the complex metabolic crosstalk between the tumour, the microenvironment and the host, which promotes disease progression to metastasis and cachexia. The metabolic relationships among the host, cancer pathogenesis and the consequent responsive systemic manifestations during cancer progression provide new perspectives for mechanistic cancer therapy and improved management of patients with cancer.

For patients with bladder cancer (BC) undergoing radical cystectomy followed by adjuvant chemotherapy, the impact of visceral adipose tissue on prognosis and chemotherapy-related toxicities has not been well established.

From July 2013 to November 2020, 224 BC patients received adjuvant gemcitabine plus cisplatin at our institution. Computed tomography images of the patients were analyzed to calculate the visceral adipose tissue index (VATI). Patients were stratified into high- and low-VATI groups based on a predetermined cutoff value, and differences in prognosis and chemotherapy-related adverse events (AEs) between the two groups were compared.

After propensity score matching, a total of 166 patients were enrolled, with 83 in the low-VATI group and 83 in the high-VATI group. The low-VATI group exhibited notably extended progression-free survival (PFS) in comparison to the high-VATI group (p = 0.044). Conversely, no substantial variation was noted concerning overall survival (OS) among the patient cohorts. In the multivariable Cox regression analysis, patients aged over 70 years (HR = 1.66, 95% CI 1.09-2.57, p = 0.04) and nodal positivity (HR = 2.98, 95% CI 1.04-4.28, p = 0.01) emerged as significant risk factors for OS. In addition to the level of VATI (HR = 2.47, 95% CI 1.02-4.21, p = 0.04), nodal positivity (HR = 4.04, 95% CI 1.30-12.56, p = 0.02) remained a significant risk factor for PFS. Regarding chemotherapy-related AEs, the most common AEs of any grade and grade ≥ 3 were hematologic toxicities. Patients in the low-VATI group exhibited a higher likelihood of experiencing grade ≥ 3 neutropenia compared to those in the high-VATI group (p = 0.04).

This study demonstrated that, among patients treated with adjuvant chemotherapy for locally advanced BC, patients in the low-VATI group exhibited a significantly prolonged PFS compared to those in the high-VATI group. However, no significant difference was observed in terms of OS. Regarding chemotherapy-related AEs, patients in the high-VATI group exhibited a relatively lower incidence and severity of toxic reactions.

The use of real-world data (RWD) in oncology is becoming increasingly important for clinical decision making and tailoring treatment. Despite the significant success of targeted therapy and immunotherapy in advanced melanoma, substantial variability in clinical responses to these treatments emphasizes the need for personalized approaches to therapy.

In this pilot study, 239 patients with melanoma were included to predict the response to both targeted therapies and immunotherapies. We used machine learning (ML) to incorporate RWD and applied explainable artificial intelligence (XAI) to explain the individual predictions.

We developed, validated, and compared four ML models to evaluate 2-year survival using RWD. Our research showed encouraging outcomes, achieving an AUC of more than 80% and an estimated accuracy of over 74% across the four ML models. The random forest model exhibited the highest performance in predicting 2-year survival with an AUC of 0.85. Local interpretable model-agnostic explanations was used to explain individual predictions and provide trust and insights into the clinical implications of the ML model.

With this proof-of-concept, we integrated RWD into predictive modeling using ML techniques to predict clinical outcomes and explore their potential implications for clinical decision making. The potential of XAI was demonstrated to enhance trust and improve the usability of the model in clinical settings. Further research, including foundation modeling and generative AI, will likely increase the predictive power of prognostic and predictive ML models in advanced melanoma.

Immune checkpoint inhibitors (ICIs) have revolutionized the management of advanced non-small cell lung cancer (NSCLC). Emerging evidence suggests a potential association between elevated body mass index (BMI) and enhanced ICI efficacy, yet this relationship remains inconclusive and warrants further investigation. This study aims to evaluate the impact of BMI on treatment efficacy and survival outcomes in advanced NSCLC patients treated with first-line ICI therapy.

A retrospective study was conducted at a multi-center registry to evaluate the impact of baseline BMI on overall survival (OS) and progression-free survival (PFS) in patients with stage IV NSCLC who received first-line ICI therapies. Treatment regimens included pembrolizumab or the combination of ipilimumab and nivolumab, administered either as monotherapy or in combination with chemotherapy, at the oncology department between January 2018 and December 2023. BMI was categorized according to the World Health Organization (WHO) classification, and OS and PFS were evaluated using Kaplan-Meier survival analysis and the Cox proportional hazards regression model.

Among 346 patients, 12.72% were underweight, 45.38% normal weight, 29.19% overweight, and 12.72% obese. Overweight and obese patients were more likely to receive pembrolizumab (p = 0.039) and less likely to undergo chemotherapy (p = 0.012). No significant differences in median overall survival (OS, log-rank: p = 0.155) or progression-free survival (PFS, log-rank: p = 0.370) were observed across BMI categories. However, differences emerged upon further analysis of PD-L1 levels (OS, log-rank: p = 0.029; PFS, log-rank: p = 0.044), additional chemotherapy (OS, log-rank: p = 0.009; PFS, log-rank: p = 0.021), type of immune checkpoint inhibitor (OS, log-rank: p < 0.001; PFS, log-rank: p < 0.001), and histologic diagnosis (OS, log-rank: p = 0.011; PFS, log-rank: p = 0.003).

BMI was not an independent predictor of survival outcomes in advanced NSCLC treated with ICI. Incorporating BMI with other patient-specific factors into personalized immunotherapy strategies highlights the importance of tailored approaches to improve patient care and clinical outcomes.

Changes in the dosing schedules for immune checkpoint inhibitors, specifically nivolumab and pembrolizumab, in the treatment of metastatic melanoma, were introduced based on pharmacokinetic data and analysis of pre-existing clinical trial data in the absence of new clinical trials. Therefore, we sought to provide real-world data examining whether fixed-dose therapy (FDT) or weight-adapted therapy (WAT) influenced progression-free (PFS) and overall survival (OS), and the incidence of immune-related adverse events (irAEs). The electronic case notes of all patients (n = 77) treated with immune checkpoint inhibitor immunotherapy (ICI) in the first-line setting for melanoma in the Department of Dermatology, University of Luebeck, between the 1 January 2017 and the 31 December 2020, were retrospectively analysed. Although a higher proportion of patients in the WAT cohort were treated in the palliative setting, there were no correlations between dosing schedule, renal function, or BMI and PFS. Moreover, there were no differences between the cohorts in terms of PFS, OS, or the number and nature of irAEs. An elevated serum S100 concentration was associated with a decreased mean PFS in the FDT cohort (p < 0.001). This study, although inherently limited by its retrospective and monocentric nature, provides reassuring evidence that dosing schedule and pre-existing comorbidities do not influence efficacy or the irAE profile of ICI therapy in the management of melanoma.

Monoclonal antibodies (mAbs) have transformed cancer treatment by providing highly targeted and effective therapies that specifically attack cancer cells, thus reducing the likelihood of adverse events (AEs) in patients. mAbs exert their action through various mechanisms, such as receptor blockade, antibody-dependent cellular cytotoxicity (ADCC), complement-dependent cytotoxicity (CDC), and inhibition of immune checkpoints (eg, PD-1, PD-L1, and CTLA-4). These therapies have led to significant improvements in the treatment of several cancers, including HER2-positive breast cancer, non-small cell lung cancer (NSCLC), and melanoma. The efficacy of mAb therapy in cancer treatment is influenced by various intrinsic and extrinsic factors, such as environmental exposures, psychosocial factors, infection status, ways of life, and tumor microenvironment (TME), all of which can impact immune responses and treatment outcomes. Notably, the therapeutic benefits of mAbs are often accompanied by immune-related AEs (irAEs), which can vary from mild to severe and affect multiple organ systems. The dual nature of mAbs-stimulating antitumor immune responses while also inducing immune-related side effects-presents a notable challenge in clinical practice. This review highlights the importance of proactive strategies for managing irAEs, such as early detection, corticosteroid use, targeted immunosuppressive treatments, and the urgent need for reliable predictive biomarkers to improve treatment outcomes. Advancements in the prevention, prediction, and management of irAEs are essential to enhance the safety and effectiveness of mAb-based therapies, ultimately aiming to improve cancer patient outcomes.

Sex-based differences have been observed in the incidence and prognosis of various cancers, as well as in the response to immune check point inhibitors (ICIs). These disparities are partially attributed to sex-based differences in the molecular characteristics of the anticancer immune response, which are largely influenced by sex hormones. Here, we provide a comprehensive overview on how sex hormones affect innate and adaptive immunity and contribute to shaping the features of tumor immune microenvironment and response to anticancer immunotherapy. We also discuss the promising potential and challenges of combining sex hormone manipulation with anticancer immunotherapy as new therapeutic strategy. We surmise that a sex-based perspective should be part of precision medicine approaches, and sex hormones manipulation provides opportunities for innovative immune therapeutic approaches.

Adipose tissue reduction is one of the features in patients with cancer cachexia. However, it remains unclear whether visceral fat area (VFA) and subcutaneous fat area (SFA) contribute differently to the progression of cancer cachexia in colon cancer patients. This study aims to investigate the prognostic impact of VFA and SFA in stage I-III colon cancer patients with cachexia.

Patients diagnosed with stage I-III colon cancer were preoperatively measured for VFA and SFA and then divided into VFA-high (VFA-H) and VFA-low (VFA-L) groups, as well as SFA-high (SFA-H) and SFA-low (SFA-L) groups. The prognostic impact of VFA and SFA for colon cancer patients with cachexia were analyzed using the Kaplan-Meier method and Cox regression analysis.

A total of 916 colon cancer patients (377 with cachexia and 539 without) were included in the study. In patients with cachexia, the estimated five-year overall survival (OS) was higher in the VFA-H group compared to the VFA-L group (p < 0.001). There was no significant difference in five-year OS between the SFA-L and SFA-H groups (p = 0.076). Cox regression analysis indicated that VFA (hazard ratio [HR] = 0.55, 95% confidence interval [CI] 0.40 to 0.76; p < 0.001) was an independent prognostic factor for patients with cachexia. SFA (HR = 0.78, 95% CI 0.59 to 1.03; p = 0.076) was not an independent prognostic factor for patients with cachexia.

Preoperative VFA, but not SFA was a useful prognostic factor for long-term outcomes in stage I-III colon cancer patients with cachexia. More attention should be paid to VFA in colon cancer patients with cachexia.

Predicting whether a patient with cancer will benefit from immune checkpoint inhibitors (ICIs) without resorting to advanced genomic or immunologic assays is an important clinical need. To address this, we developed and evaluated SCORPIO, a machine learning system that utilizes routine blood tests (complete blood count and comprehensive metabolic profile) alongside clinical characteristics from 9,745 ICI-treated patients across 21 cancer types. SCORPIO was trained on data from 1,628 patients across 17 cancer types from Memorial Sloan Kettering Cancer Center. In two internal test sets comprising 2,511 patients across 19 cancer types, SCORPIO achieved median time-dependent area under the receiver operating characteristic curve (AUC(t)) values of 0.763 and 0.759 for predicting overall survival at 6, 12, 18, 24 and 30 months, outperforming tumor mutational burden (TMB), which showed median AUC(t) values of 0.503 and 0.543. Additionally, SCORPIO demonstrated superior predictive performance for predicting clinical benefit (tumor response or prolonged stability), with AUC values of 0.714 and 0.641, compared to TMB (AUC = 0.546 and 0.573). External validation was performed using 10 global phase 3 trials (4,447 patients across 6 cancer types) and a real-world cohort from the Mount Sinai Health System (1,159 patients across 18 cancer types). In these external cohorts, SCORPIO maintained robust performance in predicting ICI outcomes, surpassing programmed death-ligand 1 immunostaining. These findings underscore SCORPIO's reliability and adaptability, highlighting its potential to predict patient outcomes with ICI therapy across diverse cancer types and healthcare settings.

Immunotherapy with checkpoint inhibitors has become the cornerstone of systemic treatment for non-oncogene addicted non-small-cell lung cancer. Despite its pivotal role, a significant proportion of patients-approximately 70-85%-either exhibit primary resistance to PD-1 blockade or develop acquired resistance following an initial benefit, even in combination with chemotherapy and/or anti-CTLA-4 agents. The phenomenon of primary and acquired resistance to immunotherapy represents a critical clinical challenge, largely based on our incomplete understanding of the mechanisms of action of immunotherapy, and the resulting lack of accurate predictive biomarkers. Here, we review the definitions and explore the proposed mechanisms of primary and acquired resistance, including those related to the tumor microenvironment, systemic factors, and intrinsic tumor characteristics. We also discuss translational data on adaptive changes within tumor cells and the immune infiltrate following exposure to checkpoint inhibitors. Lastly, we offer a comprehensive overview of current and emerging therapeutic strategies designed to prevent primary resistance and counteract acquired resistance.

Triple-negative breast cancer (TNBC), which tends to be more advanced when diagnosed and more aggressive than other breast cancer subtypes, is accelerated by obesity. Hypertrophic adipocytes and cancer cells exhibit increased oxidative stress and altered redox homeostasis, influencing therapeutic outcomes. Enzymes implicated in both redox regulation and TNBC include glutathione peroxidase 4 (GPX4; reduces lipid peroxides) and pyruvate carboxylase (PC; essential in oxidative stress protection). Using preclinical models, we characterized interactions between GPX4, PC, and oxidative stress in TNBC cells, and established effects of GPX4 suppression on TNBC progression. In TNBC cells, PC knockdown increased GPX4 expression, while GPX4 knockdown increased PC expression. GPX4 inhibition by erastin or RSL3 enhanced TNBC cell death in vitro, and antioxidants mitigated the cytotoxicity. In obese mice, GPX4 knockdown, versus scramble control: (i) reduced tumor burden following orthotopic transplantation of TNBC cells; and (ii) reduced lung metastasis following tail vein injection of TNBC cells in combination with chemotherapy (carboplatin) but not immunotherapy (anti-CTLA4 plus anti-PD1). We conclude that GPX4 and PC expression are inversely related in TNBC cells, and GPX4 and obesity interact to impact TNBC progression and treatment responses. Moreover, GPX4-mediated redox defense, alone or in combination with chemotherapy, is a targetable vulnerability for treating TNBC, including obesity-related TNBC.

GPX4 suppression, alone or with current TNBC therapies, impacts outcomes in preclinical TNBC models with or without obesity and offers a new, plausible mechanistic target for TNBC treatment.

Obesity, a global health concern, is associated with severe health issues like type 2 diabetes, heart disease, and respiratory complications. It also increases the risk of various cancers, including melanoma, endometrial, prostate, pancreatic, esophageal adenocarcinoma, colorectal carcinoma, renal adenocarcinoma, and pre-and post-menopausal breast cancer. Obesity-induced cellular changes, such as impaired CD8+ T cell function, dyslipidemia, hypercholesterolemia, insulin resistance, mild hyperglycemia, and fluctuating levels of leptin, resistin, adiponectin, and IL-6, contribute to cancer development by promoting inflammation and creating a tumor-promoting microenvironment rich in adipocytes. Adipocytes release leptin, a pro-inflammatory substance that stimulates cancer cell proliferation, inflammation, and invasion, altering the tumor cell metabolic pathway. Adiponectin, an insulin-sensitizing adipokine, is typically downregulated in obese individuals. It has antiproliferative, proapoptotic, and antiangiogenic properties, making it a potential cancer treatment. This narrative review offers a comprehensive examination of the molecular interconnections between obesity and cancer, drawing on an extensive, though non-systematic, survey of the recent literature. This approach allows us to integrate and synthesize findings from various studies, offering a cohesive perspective on emerging themes and potential therapeutic targets. The review explores the metabolic disturbances, cellular alterations, inflammatory responses, and shifts in the tumor microenvironment that contribute to the obesity-cancer link. Finally, it discusses potential therapeutic strategies aimed at disrupting these connections, offering valuable insights into future research directions and the development of targeted interventions.

Immune-based combinations are the cornerstone of the first-line treatment of metastatic renal cell carcinoma patients, leading to outstanding outcomes. Nevertheless, primary resistance and disease progression is a critical clinical challenge. To properly address this issue, it is pivotal to understand the mechanisms of resistance to immunotherapy and tyrosine kinase inhibitors, that tumor eventually develop under treatment. In this review of the literature, we aim at exploring resistance mechanisms arising in patients treated with first-line immune-based combinations in order to understand the biological pattern that should be investigated to overcome them. In more detail, mechanisms of resistance to nivolumab and pembrolizumab are divided into intrinsic to cancer cells and extrinsic (stromal or immune cells). Regarding axitinib, the increased expression of Nuclear protein 1 (NUPR1) or decreased levels of insulin receptor (INSR) characterize resistant cells. The secretion of non-VEGF pro-angiogenic factors, such as PDGF-BB, IL-1β, MMP-9, Gro-α, IL-8, IL-6, and CCL-2, can lead to resistance to cabozantinib. The reactivation of pathways previously targeted by lenvatinib or the activation of alternative pathways, such as EGFR-PAK2-ERK pathway, underlie the development of resistance to lenvatinib. Exploring resistance mechanism that arise during first-line therapy can lead to the development of treatment strategy able to overcome them in order to improve duration of response and patients outcomes.

In recent years, immunotherapy using immune checkpoint inhibitors (ICIs) has revolutionized the treatment of advanced malignancies. As such, numerous ICIs are establishing themselves as prospective therapy alternatives for individuals with head and neck cancer (HNC). Evidence suggests a potential correlation between body mass index (BMI) and the efficacy of ICIs in cancer patients. However, this association in HNC patients subjected to immunotherapy is still unclear.

To investigate the effect of BMI on the survival outcomes of HNC patients treated with immunotherapy.

PubMed, Web of Science, and Google Scholar databases were searched extensively for records published until January 2024. Full-text articles aligned with the research objective were included, while records published in English, case reports, reviews, editorials, and studies reporting immunotherapy combined with other cancer therapies were excluded. The data required for review and analysis was abstracted in Excel files by two independent reviewers. Additionally, data synthesis was carried out using the Review Manager program, and evaluation of methodological quality was done with the Newcastle Ottawa scale. The statistical analyses were stratified according to the BMI values, of which patients were categorized as follows: Obese (BMI ≥ 27.5), non-obese (BMI < 27.5), overweight (BMI: 23.5-27.5), underweight (BMI < 18.5), normal (BMI: 18.5-23.5), low (BMI < 20), and high (BMI ≥ 20).

Only six studies were reviewed and analyzed. A subgroup analysis of data from these studies showed that obese HNC patients on immunotherapy had significantly better overall survival (OS) rates than non-obese patients (HR: 0.51; 95% CI: 0.29-0.93; p = 0.03). However, the progression-free survival (PFS) was statistically similar between obese and non-obese patients (HR: 0.72; 95% CI: 0.39-1.33; p = 0.30). In addition, when BMI was stratified as either low or high, no significant difference was observed in the OS and PFS of HNC patients (HR: 0.99; 95% CI: 0.59-1.66; p = 0.97 and HR: 0.93; 95% CI: 0.61-1.41; p = 0.42, respectively). Similarly, the statistical analyses showed that overweight patients have similar OS and PFS as patients with normal BMI (HR: 0.53; 95% CI: 0.15-1.92; p = 0.33 and HR: 0.55; 95% CI: 0.20-1.52; p = 0.25, respectively). In contrast, underweight patients demonstrated poor OS and PFS (HR: 2.56; 95% CI: 1.29-5.12; p = 0.008 and HR: 2.76; 95% CI: 1.17-6.52; p = 0.02, respectively).

Obese HNC patients on immunotherapy tend to have improved OS than non-obese patients, while underweight patients have worse clinical prognoses than those with normal or above BMI.

Cancer heterogeneity is a major challenge in oncology, complicating diagnosis, prognostication, and treatment. The clinical heterogeneity of cancer, which leads to differential treatment outcomes between patients with histopathologically similar cancers, is attributable to molecular diversity manifesting through genetic, epigenetic, transcriptomic, microenvironmental, and host biology differences. Heterogeneity is observed between patients, individual metastases, and within individual lesions. This review discusses clinical implications of heterogeneity, emphasizing need for personalized approaches to overcome challenges posed by cancer's diverse presentations. Understanding of emerging molecular diagnostic and analytical techniques can provide a view into the multidimensional complexity of cancer heterogeneity. With over 90% of cancer-related deaths associated with metastasis, we additionally explore the role heterogeneity plays in treatment resistance and recurrence of metastatic lesions. Molecular insights from next-generation sequencing, single-cell transcriptomics, liquid biopsy technology, and artificial intelligence will facilitate the development of combination therapy regimens that can potentially induce lasting and even curative treatment outcomes.

Obesity is a risk factor for developing cancer but is also associated with improved outcomes after treatment with immune checkpoint inhibitors (ICIs), a phenomenon called the obesity paradox. To interrogate mechanisms of divergent immune responses in obese and non-obese patients, we examined the relationship among obesity status, clinical responses, and immune profiles from a diverse, pan-tumor cohort of patients treated with ICI-based therapy.

From June 2021 to March 2023, we prospectively collected serial peripheral blood samples from patients with advanced or metastatic solid tumors who received ICI as standard of care at Johns Hopkins. Patients were stratified by obesity status at treatment initiation, with obesity defined as body mass index (BMI)≥30 at treatment initiation and BMI≥18.5 and <30 considered non-obese; underweight patients (BMI<18.5) were excluded. We evaluated the concentration of 37 cytokines and used cytometry by time of flight to characterize immune cell clusters and cell-surface expression markers at baseline and on-treatment.

We enrolled 94 patients, of whom 30 (32%) were obese and 64 (68%) were non-obese. Compared with non-obese patients, obese patients had superior progression-free survival (HR: 0.44 (95% CI: 0.24 to 0.81), p=0.01) and overall survival (OS) (HR: 0.24 (95% CI: 0.07 to 0.80), p=0.02). Obese patients had lower serum IL-15 levels at treatment baseline and lower on-treatment levels of IL-6, IL-8, and IL-15. Low on-treatment IL-6 was associated with improved OS (HR: 0.27 (95% CI: 0.08 to 0.88), p=0.03), as was low on-treatment IL-8 (HR: 0.19 (95% CI: 0.05 to 0.70), p=0.01). Obese patients demonstrated lower levels of T effector cells with reduced expression of cytotoxicity markers and higher expression of exhaustion markers at baseline and on-treatment.

Obese and non-obese patients with cancer have divergent immunological responses to ICIs. Obesity is associated with reduced levels of certain inhibitory cytokines and higher expression of T-cell exhaustion markers. ICI-based therapy may more effectively reverse T-cell dysfunction in obese patients, potentially contributing to the paradoxically improved responses in this population.

Cancer immunotherapy-including immune checkpoint inhibition (ICI) and adoptive cell therapy (ACT)-has become a standard, potentially curative treatment for a subset of advanced solid and liquid tumors. However, most patients with cancer do not benefit from the rapidly evolving improvements in the understanding of principal mechanisms determining cancer immune responsiveness (CIR); including patient-specific genetically determined and acquired factors, as well as intrinsic cancer cell biology. Though CIR is multifactorial, fundamental concepts are emerging that should be considered for the design of novel therapeutic strategies and related clinical studies. Recent advancements as well as novel approaches to address the limitations of current treatments are discussed here, with a specific focus on ICI and ACT.

The last decade has witnessed unprecedented succusses with the use of immune checkpoint inhibitors in treating cancer. Nevertheless, the proportion of patients who respond favorably to the treatment remained rather modest, partially due to treatment resistance. This has fueled a wave of research into potential mechanisms of resistance to immune checkpoint inhibitors which can be classified into primary resistance or acquired resistance after an initial response. In the current review, we summarize what is known so far about the mechanisms of resistance in terms of being tumor-intrinsic or tumor-extrinsic taking into account the multimodal crosstalk between the tumor, immune system compartment and other host-related factors.

Aging is associated with a decline in immune function, termed immunosenescence, which compromises host defences and increases susceptibility to infections and cancer. Physical exercise is widely recognized for its myriad health benefits, including the potential to modulate the immune system. This review explores the bidirectional relationship between immunosenescence and physical exercise, focusing on their interplay in shaping antitumor immunity. We summarize the impact of aging on innate and adaptive immune cells, highlighting alterations that contribute to immunosenescence and cancer development. We further delineate the effects of exercise on immune cell function, demonstrating its potential to mitigate immunosenescence and enhance antitumor responses. We also discuss the implications of immunosenescence for the efficacy of immunotherapies, such as immune checkpoint inhibitors and adoptive T cell therapy, and explore the potential benefits of combining exercise with these interventions. Collectively, this review underscores the importance of understanding the complex relationship between immunosenescence, physical exercise, and antitumor immunity, paving the way for the development of innovative strategies to improve cancer outcomes in the aging population.

Lung cancer is a pathology with an important incidence. It is a multifactorial disease characterized by epigenetic and nutritional factors. Indeed, there is a strong association between adipose tissue and the pulmonary system, and low-grade inflammation of obese and/or overweight subjects have a pivotal role in lung cancer establishment.

In this study, we analyzed body composition through bioelectrical impedance analysis (BIA) and biochemical parameters such as glycemic and lipidic profile, inflammation profile and adiponectin serum levels in 30 patients (19 male; 11 women) undergoing video-assisted thoracoscopic surgery (VATS) lobectomy for lung cancer from September 2021 to May 2022 at the Thoracic Unit of Luigi Vanvitelli University of Naples. A control group were also recruited (15 male; 15 female) consisting of age and sex matched volunteered subjects at the Thoracic Unit of Luigi Vanvitelli University of Naples. The control group and lung cancer patients were monitored for anthropometric and biochemical parameters before VATS lobectomy. Furthermore, the lung cancer patients were also monitored after 6 months of surgery.

Body composition is modified after surgery and also albumin and C-reactive protein (CRP) serum levels. In the overweight patients in our study, adiponectin levels were found to be reduced compared with the control group and increased in the same patients after VATS lobectomy.

Tumor removal as well as weight loss could affect adiponectin levels, and thus also a reduction in inflammation. In addition, weight loss could also be due to a psychological condition given by the intervention and not to malnutrition related to therapy.

IntroductionObesity is a risk factor for the development of renal cell carcinoma (RCC), however observational studies have suggested patients with RCC receiving systemic anti-cancer therapy (SACT) and BMI ≥25 kg/m2 may have a better prognosis than patients with a normal or low BMI, a phenomenon often referred to as the obesity paradox.MethodsThe impact of BMI on survival outcomes in patients with advanced clear cell RCC receiving SACT within the National Health Service (NHS) in England between 2010 and 2018 was investigated. A retrospective analysis was performed using the SACT dataset from NHS-England.ResultsA total of 1034 patients were included. The majority of patients commenced treatment with oral SACT, pazopanib (53.3%) and sunitinib (43.7%). Median overall survival for patients with BMI ≤25 kg/m2 was 12.6 months (95% CI; 10.1-14.4) and 17.9 months (15.4-20.0) for patients with BMI ≥25 kg/m2 (P < .001). The association between BMI and improved survival was greatest in the first year of commencing SACT with the adjusted mortality rate of 68.9% for patients with BMI less than 25 kg/m2 compared to 48.6% for patients with BMI greater than 25 kg/m2 (rate ratio .77, .63 to .93).ConclusionA high BMI compared to a normal or low BMI was associated with improved survival in patients with metastatic RCC who were predominantly treated with oral SACT. Improved survival in obese patients with advanced RCC may be associated with improved response to systemic targeted therapies.

This hypothesis-generating study aims to examine the extent to which computed tomography-assessed body composition phenotypes are associated with immune and phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) signaling pathways in breast tumors. A total of 52 patients with newly diagnosed breast cancer were classified into four body composition types: adequate (lowest two tertiles of total adipose tissue [TAT]) and highest two tertiles of total skeletal muscle [TSM] areas); high adiposity (highest tertile of TAT and highest two tertiles of TSM); low muscle (lowest tertile of TSM and lowest two tertiles of TAT); and high adiposity with low muscle (highest tertile of TAT and lowest tertile of TSM). Immune and PI3K/AKT pathway proteins were profiled in tumor epithelium and the leukocyte-enriched stromal microenvironment using GeoMx (NanoString). Linear mixed models were used to compare log2-transformed protein levels. Compared with the normal type, the low muscle type was associated with higher expression of INPP4B (log2-fold change = 1.14, p = 0.0003, false discovery rate = 0.028). Other significant associations included low muscle type with increased CTLA4 and decreased pan-AKT expression in tumor epithelium, and high adiposity with increased CD3, CD8, CD20, and CD45RO expression in stroma (p < 0.05; false discovery rate > 0.2). With confirmation, body composition can be associated with signaling pathways in distinct components of breast tumors, highlighting the potential utility of body composition in informing tumor biology and therapy efficacies.

Background: Limited data are available on the frequency and significance of body weight loss during cancer therapy. This study investigated the frequency of patients who experienced body weight loss during immune checkpoint inhibitor (ICI) plus chemotherapy for advanced non-small cell lung cancer (NSCLC) and the impact of weight loss on treatment outcomes. Methods: Using the clinical data of 370 patients with NSCLC who received a combination of ICI and chemotherapy at 13 institutions, this study investigated the frequency of body weight loss > 5% during treatment and determined the impact of body weight loss on patient outcomes. Results: Of the 370 included patients, 141 (38.1%) lost more than 5% of their body weight during ICI plus chemotherapy (WL group). The 2-month landmark analysis showed that patients who experienced body weight loss of >5% during treatment had worse overall survival (OS) and progression-free survival (PFS) than those who did not (OS 14.0 and 31.1 months in the WL non-WL groups, respectively, p < 0.001; PFS 6.8 and 10.9 months in the WL non-WL groups, respectively, p = 0.002). Furthermore, a negative impact of body weight loss on survival was observed even in those who had obesity (body mass index [BMI] ≥ 25.0) at the start of therapy (OS 12.8 and 25.4 months in the WL non-WL groups, respectively, p < 0.001; PFS 5.7 and 10.7 months in the WL non-WL groups, respectively, p = 0.038). Conclusions: In conclusion, weight loss of >5% during ICI plus chemotherapy negatively influenced patient outcomes. Further and broader studies should investigate the role of nutritional status, specifically weight change and nutritional support, in responsiveness to ICI plus chemotherapy.

The primary objective of this study was to assess the frequency of body composition increases and their relationships to changes in body weight in two cohorts of real world, treatment-naïve, advanced non-small cell lung cancer (NSCLC) patients. One cohort received the current standard of care (CSOC), which consisted of immunotherapy and newer chemotherapy regimens, and the other cohort was treated with the former standard of care (FSOC), consisting only of older platinum-containing regimens.

CSOC (n = 106) and FSOC (n = 88) cohorts of advanced NSCLC patients were included in this study. Weights were collected at each clinical visit, and body composition analysis from routine chest computed tomography via automated segmentation software assessed at baseline and at 6 and 12 weeks. Standard statistical methods were used to calculate relationships between changes in weight and in body composition.

The CSOC cohort contained 106 stage IV NSCLC patients treated between 16/12/2014 and 22/10/2020 while the FSOC cohort contained 88 stage III/IV NSCLC patients treated between 16/6/2006 and 18/11/2014. While each cohort exhibited decreases in median weight, body mass index (BMI), mean skeletal muscle index (SMI) and subcutaneous adipose tissue index (SATI) at the 6 and 12 week time points, a subset of patients experienced increases in these parameters. Using a threshold of ≥2.5% increase for weight, BMI, SMI, and SATI at the 12 week time point, both cohorts showed similar (20.5% and 27.3%) increases in these parameters. With a cut point of ≥5% increase at 12 weeks follow-up, 8.0% to 25.0% of the patients gained ≥5% in weight, BMI, SMI and SATI. Comparing these results in each cohort showed no significant differences. Pearson coefficients for weight change related to changes in SMI and SATI at 6 and 12 weeks ranged from 0.31 to 0.58 with all P values <0.02. Pearson coefficients for weight change at 12 weeks related to changes in VATI and IMATI ranged from 0.26 to 0.47 with all P values <0.05. Comparison of Pearson coefficients for each cohort showed no significant differences.

Although decreases in median weight, BMI, SMI and SATI were observed in both cohorts, similar percentage of patients in each cohort experienced increases in these parameters. These findings, plus the positive correlations between longitudinal measurements of weight, muscle mass and adipose tissue, indicate that weight gain in these patients involves increases in both muscle mass and adipose tissue. Upon validation, these findings could have implications for clinical trial design and for translational research in cancer cachexia.

Use of immune checkpoint inhibitors (ICIs) as cancer immunotherapy has advanced rapidly in the clinic; however, mechanisms underlying resistance to ICI therapy, including impaired T cell infiltration, low immunogenicity, and tumor "immunophenotypes" governed by the host, remain unclear. We previously reported that in some cancer contexts, tumor cell-derived angiopoietin-like protein 2 (ANGPTL2) has tumor-promoting functions. Here, we asked whether ANGPTL2 deficiency could enhance antitumor ICI activity in two inflammatory contexts: a murine syngeneic model of colorectal cancer and a mouse model of high-fat diet (HFD)-induced obesity. Systemic ANGPTL2 deficiency potentiated ICI efficacy in the syngeneic model, supporting an immunosuppressive role for host ANGPTL2. Relevant to the mechanism, we found that ANGPTL2 induces pro-inflammatory cytokine production in adipose tissues, driving generation of myeloid-derived suppressor cells (MDSCs) in bone marrow and contributing to an immunosuppressive tumor microenvironment and resistance to ICI therapy. Moreover, HFD-induced obese mice showed impaired responsiveness to ICI treatment, suggesting that obesity-induced chronic inflammation facilitated by high ANGPTL2 expression blocks ICI antitumor effects. Our findings overall provide novel insight into protumor ANGPTL2 functions and illustrate the essential role of the host system in ICI responsiveness.